Cytokine inhibitors

ABSTRACT

Disclosed are compounds of formula (I)  
                 
which inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

APPLICATION DATA

This application claims benefit to U.S. provisional application No.60/567,693 filed May 3, 2004.

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates to compounds of formula (I)

The compounds of the invention inhibit production of cytokines involvedin inflammatory processes and are thus useful for treating diseases andpathological conditions involving inflammation such as chronicinflammatory disease. This invention also relates to processes forpreparing these compounds and to pharmaceutical compositions comprisingthese compounds.

2. Background Information

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines which play a role in cytokine mediated diseases. These, alongwith several other related molecules, mediate the inflammatory responseassociated with the immunological recognition of infectious agents. Theinflammatory response plays an important role in limiting andcontrolling pathogenic infections.

Elevated levels of proinflammatory cytokines are also associated with anumber of diseases of autoimmunity such as toxic shock syndrome,rheumatoid arthritis, osteoarthritis, diabetes and inflammatory boweldisease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). Inthese diseases, chronic elevation of inflammation exacerbates or causesmuch of the pathophysiology observed. For example, rheumatoid synovialtissue becomes invaded with inflammatory cells that result indestruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest.Med. 43: 28-38). Studies suggest that inflammatory changes mediated bycytokines may be involved in endothelial cell pathogenesis includingrestenosis after percutaneous transluminal coronary angioplasty (PTCA)(Tashiro, H., et al., 2001 March, Coron Artery Dis 12(2): 107-13). Animportant and accepted therapeutic approach for potential drugintervention in these diseases is the reduction of proinflammatorycytokines such as TNF (also referred to in its secreted cell-free formas TNFα) and IL-1β. A number of anti-cytokine therapies are currently inclinical trials. Efficacy has been demonstrated with a monoclonalantibody directed against TNFα in a number of autoimmune diseases(Heath, P., “CDP571: An Engineered Human IgG4 Anti-TNFα Antibody” IBCMeeting on Cytokine Antagonists, Philadelphia, Pa., Apr. 24-5, 1997).These include the treatment of rheumatoid arthritis, Crohn's disease andulcerative colitis (Rankin, E. C. C., et al., 1997, British J. Rheum.35: 334-342 and Stack, W. A., et al., 1997, Lancet 349: 521-524). Themonoclonal antibody is thought to function by binding to both solubleTNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG 1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46:S143).

IL-1 has been implicated as an immunological effector molecule in alarge number of disease processes. IL-1 receptor antagonist (IL-1ra) hadbeen examined in human clinical trials. Efficacy has been demonstratedfor the treatment of rheumatoid arthritis (Antril, Amgen). In a phaseIII human clinical trial IL-Ira reduced the mortality rate in patientswith septic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitusshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24).

Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, inhibitorsof cytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease.

Elevation of several cytokines have been demonstrated during activeinflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1and IL-1ra is present in patients with IBD. Insufficient production ofendogenous IL-Ira may contribute to the pathogenesis of IBD (Cominelli,et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease ischaracterized by the presence of beta-amyloid protein deposits,neurofibrillary tangles and cholinergic dysfunction throughout thehippocampal region. The structural and metabolic damage found inAlzheimer disease is possibly due to a sustained elevation of IL-1(Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in thepathogenesis of human immunodeficiency virus (HIV) has been identified.IL-1ra showed a clear relationship to acute inflammatory events as wellas to the different disease stages in the pathophysiology of HIVinfection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 andTNF are both involved in periodontal disease. The destructive processassociated with periodontal disease may be due to a disregulation ofboth IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.In a study of patients presenting at a hospital with sepsis, acorrelation was found between TNFα and IL-6 levels and septiccomplications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFαhas also been implicated in cachexia and muscle degradation, associatedwith HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289).Obesity is associated with an increase incidence of infection, diabetesand cardiovascular disease. Abnormalities in TNFα expression have beennoted for each of the above conditions (Loffreda, et al., 1998, FASEB J12, 57). It has been proposed that elevated levels of TNFα are involvedin other eating related disorders such as anorexia and bulimia nervosa.Pathophysiological parallels are drawn between anorexia nervosa andcancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). Aninhibitor of TNFα production, HU-211, was shown to improve the outcomeof closed brain injury in an experimental model (Shohami, et al., 1997,J Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242).

TNFα levels are elevated in airways of patients with chronic obstructivepulmonary disease and it may contribute to the pathogenesis of thisdisease (M. A. Higham et al., 2000, Eur. Respiratory J, 15, 281).Circulating TNFα may also contribute to weight loss associated with thisdisease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med.,161 (4 Pt 1), 1179). Elevated TNFα levels have also been found to beassociated with congestive heart failure and the level has beencorrelated with severity of the disease (A. M. Feldman et al., 2000, J.Amer. College of Cardiology, 35, 537). In addition, TNFα has beenimplicated in reperfusion injury in lung (Boresson et al., 2000, Amer.J. Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation,69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844,192).

TNFα is also a potent osteoclastogenic agent and is involved in boneresorption and diseases involving bone resorption (Abu-Amer et al.,2000, J. Biol. Chem., 275, 27307). It has also been found highlyexpressed in chondrocytes of patients with traumatic arthritis(Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα hasalso been shown to play a key role in the development ofglomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78,1625).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. Blocking antibodies against IL-8 havedemonstrated a role for IL-8 in the neutrophil associated tissue injuryin acute inflammation (Harada et al., 1996, Molecular Medicine Today 2,482). Therefore, an inhibitor of IL-8 production may be useful in thetreatment of diseases mediated predominantly by neutrophils such asstroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingenterocolitis.

Rhinovirus triggers the production of various proinflammatory cytokines,predominantly IL-8, which results in symptomatic illnesses such as acuterhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia andreperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dementia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including burn-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, J R CollPhysicians Lond 32, 56).

Interferon γ (IFN γ) has been implicated in a number of diseases. It hasbeen associated with increased collagen deposition that is a centralhistopathological feature of graft-versus-host disease (Parkman, 1998,Curr Opin Hematol. 5, 22). Following kidney transplantation, a patientwas diagnosed with acute myelogenous leukemia. Retrospective analysis ofperipheral blood cytokines revealed elevated levels of GM-CSF and IFN γ.These elevated levels coincided with a rise in peripheral blood whitecell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). Thedevelopment of insulin-dependent diabetes (Type 1) can be correlatedwith the accumulation in pancreatic islet cells of T-cells producing IFNγ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γ along with TNF,IL-2 and IL-6 lead to the activation of most peripheral T-cells prior tothe development of lesions in the central nervous system for diseasessuch as multiple sclerosis (MS) and AIDS dementia complex (Martino etal., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result inarterial disease that can lead to cardiac and cerebral infarction. Manyactivated immune cells are present in these lesions, mainly T-cells andmacrophages. These cells produce large amounts of proinflammatorycytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to beinvolved in promoting apoptosis or programmed cell death of thesurrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al.,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 261). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN 7 is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilbourn, et al., 1997, Dis Mon. 43, 277). IFN 7is required for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). Anelevated level of serum IgE is associated with various atopic diseasessuch as bronchial asthma and atopic dermatitis. The level of IFN γ wasnegatively correlated with serum IgE suggesting a role for IFN 7 inatopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).

WO 01/01986 discloses particular compounds alleged to having the abilityto inhibit TNF-alpha. Certain compounds disclosed in WO 01/01986 areindicated to be effective in treating the following diseases: dementiaassociated with HIV infection, glaucoma, optic-neuropathy, opticneuritis, retinal ischemia, laser induced optic damage, surgery ortrauma-induced proliferative vitreoretinopathy, cerebral ischemia,hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbonmonoxide or manganese or cyanide poisoning, Huntington's disease,Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosisand other demyelinating diseases, amyotrophic lateral sclerosis, headand spinal cord trauma, seizures, convulsions, olivopontocerebellaratrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-relatedneuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke'sencephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia,hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyricaminoaciduria, sulfite oxidase deficiency, combined systems disease,lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drugaddiction, drug tolerance, drug dependency, depression, anxiety andschizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatorycytokines including TNFα are allegedly useful for treating acute andchronic inflammation in the lung caused by inhalation of smoke such ascigarette smoke. TNFα anatagonists are apparently also useful for thetreatment of endometriosis, see EP 1022027 A1. Infliximab, in clinicaltrials for RA, has also been indicated to be useful for treating variousinflammatory diseases including Behcet's disease, uveitis and ankylosingspondylitis. Pancreatitis may also be regulated by inflammatory mediatorproduction, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998 Sep.10(3):160-75. p38MAP kinase pathway plays an role in B.burgdorferi-elicited infammation and may be useful in treatinginflammation induced by the Lyme disease agent. Anguita, J. et. al., TheJournal of Immunology, 2002, 168:6352-6357.

Compounds which modulate release of one or more of the aforementionedinflammatory cytokines can be useful in treating diseases associatedwith release of these cytokines. For example, WO 98/52558 disclosesheteroaryl urea compounds which are indicated to be useful in treatingcytokine mediated diseases. WO 99/23091 discloses another class of ureacompounds which are useful as anti-inflammatory agents. WO 99/32463relates to aryl ureas amd their use in treating cytokine diseases andproteolytic enzyme mediated disease. WO 00/41698 discloses aryl ureassaid to be useful in treating p38 MAP kinase diseases.

Compounds active against p38 MAP kinase can also be useful for treatingvarious types of cancers as described in WO 03/068223.

U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclicsubstituted urea compounds which are described as being useful fortreating hypercholesterolemia and atheroclerosis. Di-substituted aryland heteroaryl compounds are also disclosed in U.S. Pat. Nos. 6,080,763;6,319,921; 6,297,381 and 6,358,945. The compounds in the patents arealleged to possess anti-cytokine activity and are therefore useful intreating diseases associated with inflammation.

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of cytokine mediateddiseases. Therefore a need exists for small molecule inhibitors fortreating these diseases with optimized efficacy, pharmacokinetic andsafety profiles.

BRIEF SUMMARY OF THE INVENTION

The work cited above supports the principle that inhibition of cytokineproduction with small molecule compounds will be beneficial in thetreatment of various disease states.

It is therefore an object of the invention to provide compounds offormula (I)

It is a further object of the invention to provide methods for treatingcytokine mediated diseases and pathological conditions involvinginflammation such as chronic inflammatory disease, using the novelcompounds of the invention.

It is yet a further object of the invention to provide pharmaceuticalcompositions and processes of preparation of the above-mentioned novelcompounds.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a broad generic aspect of the invention there is provided a compoundof the formula (I)

wherein:

-   Ar¹ is chosen from rings (i), (ii) and (iii) below:    wherein one of A or B is nitrogen and the other is carbon, R¹ is    covalently attached to either A or B, and when nitrogen is N—R¹ the    double bond between A and B is not present;-   R₁ is chosen from hydrogen, NO₂, —N(R^(c))₂, J-C(O)—N(R^(c))—,    J-S(O)_(m)—N(R^(c))—,    -   or R¹ is chosen from C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl        or C₃₋₇ cycloalkoxyl, C₁₋₅ alkylthiol or C₃₋₇ cycloalkylthiol,        C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino,        C₂₋₅ alkenyl, C₂₋₅ alkynyl, heterocycle, heteroaryl and nitrile,        each of the aforementioned where possible are optionally        partially or fully halogenated or are optionally further        substituted with alkylsulfonylamino, alkoxyl, amino, alkylamino,        dialkylamino, hydroxyl, oxo, nitro or nitrile;    -   or R¹ is, where P can be 0, >CR⁹ or >NR⁹    -   wherein z is 1 to 4, preferably 1 to 2,    -   R⁹ is chosen from C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl or        C₃₋₇ cycloalkoxyl, C₁₋₅ alkylthiol or C₃₋₇ cycloalkylthiol, C₁₋₅        acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₂₋₅        alkenyl, C₂₋₅ alkynyl, heterocycle, heteroaryl and nitrile, each        of the aforementioned where possible are optionally partially or        fully halogenated or are optionally further substituted with        alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,        hydroxyl, oxo, nitro or nitrile;    -   R² is chosen from hydrogen, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy,        C₁₋₅ alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyl, oxo, C₁₋₅        alkylS(O)_(m)— and amino optionally mono- or di-substituted by        C₁₋₅ alkyl, aryl or aryl C₁₋₅ alkyl;        wherein-   R^(1′) is chosen from hydrogen, C₁₋₅ alkylS(O)_(m)—, C₁₋₆ alkyl,    C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl or C₃₋₇ cycloalkoxyl, C₁₋₅ alkylthiol    C₃₋₇ cycloalkylthiol, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy,    C₂₋₅ alkenyl, C₂₋₅ alkynyl, heterocycle, heterocycleC₁₋₆ alkyl,    heteroaryl, heteroarylC₁₋₆ alkyl and nitrile, each of the    aforementioned where possible are optionally partially or fully    halogenated or are optionally further substituted with    alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,    hydroxyl, oxo, nitro or nitrile;-   R^(2′), is chosen from nitrile, C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—,    NH₂—C(O)—(CH₂)_(n)—, H, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₁₋₅    alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyl and amino optionally    mono- or di-substituted by C₁₋₅ alkyl, aryl or aryl C₁₋₅ alkyl;    wherein c is a benzo ring fused to ring d which is a 5-7 membered    heterocyclic ring;-   each R^(x) is chosen from C₁₋₆ alkyl or C₃₋₇ cycloalkyl each being    optionally substituted by C₁₋₃ alkyl and optionally partially or    fully halogenated, C₁₋₄ acyl, aroyl, C₁₋₄ alkoxy, which may    optionally be partially or fully halogenated, halogen, C₁₋₆    alkoxycarbonyl, carbocyclesulfonyl and —SO₂—CF₃;-   each J is independently chosen from C₁₋₁₀ alkyl and carbocycle each    optionally substituted by R^(b);-   R^(b) is chosen from hydrogen, C₁₋₅ alkyl, hydroxyC₁₋₅ alkyl, C₂₋₅    alkenyl, C₂₋₅ alkynyl, carbocycle, heterocycle, heteroaryl, C₁₋₅    alkoxy, C₁₋₅ alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅ dialkylamino,    C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, each    of the aforementioned are optionally partially or fully halogenated,    or R^(b) is chosen from C₁₋₅ alkylsulphonylamino, hydroxy, oxo,    halogen, nitro and nitrile;-   Q is a N or CR^(p);-   Y is >CR^(p)R^(v), —CR^(p)═C(R^(v))—, —O—, —N(R^(c))— or >S(O)_(m);-   each R^(c), R^(p), R^(v) and R^(y) are each independently hydrogen    or C₁₋₅ alkyl;-   X is —CH₂—, —N(R^(c))—, —O— or —S—;-   W is N or CH;-   each m independently 0, 1 or 2;-   n is 1-4;-   each R³, R⁴ and R⁵ are independently chosen from hydrogen, C₁₋₆    alkyl and halogen;-   R⁶ is optionally attached at a position ortho or meta to the N atom    of the indicated ring, and is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, >C(O), —NH—, —C(O)—NH—, —S—, C₁₋₅ alkyl    branched or unbranched, C₂₋₅ alkenyl, C₁₋₃ acyl, C₁₋₃ alkyl(OH),    heterocycle selected from morpholinyl, piperazinyl, piperidinyl,    pyrrolidinyl and tetrahydrofuranyl, heteroaryl selected from    pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,    imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl,    oxazolyl and isothiazolyl or aryl each alkyl, alkenyl, acyl,    heterocycle, heteroaryl and aryl are optionally substituted by one    to three hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl,    —NR⁷R⁸ or NR⁷R⁸—C(O)—-   wherein each R⁶ is further optionally covalently attached to groups    chosen from:    -   hydrogen, NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy,        C₁₋₃ alkoxy, phenoxy, benzyloxy, arylC₀₋₄ alkyl, heteroaryl C₀₋₄        alkyl and heterocycle C₀₋₄alkyl, each above-listed heterocycle,        heteroaryl and aryl group is optionally substituted by one to        three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅        alkoxycarbonyl, NR⁷R⁸—C(O)— or C₁₋₄ acyl;        each R⁷ and R⁸ are independently hydrogen, phenylC₀₋₃alkyl        optionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl        amino, or R⁷ and R⁸ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or        unbranched alkyl optionally substituted by C₁₋₄ alkoxy, hydroxy        or mono or diC₁₋₃ alkyl amino;        or the pharmaceutically acceptable salts and/or isomers thereof.

In another embodiment there is provided a compound of the invention asdescribed immediately above and wherein:

-   if Ar¹ is (i) then:-   R¹ is chosen from hydrogen, C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅    alkoxyl and nitrile, each of the aforementioned where possible are    optionally partially or fully halogenated or are optionally further    substituted with alkylsulfonylamino, alkoxyl, amino, alkylamino,    dialkylamino, hydroxyl, oxo, nitro or nitrile;-   R² is chosen from hydrogen, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₁₋₅    alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyl, oxo, C₁₋₅    alkylS(O)_(m)— and amino optionally mono- or di-substituted by C₁₋₅    alkyl, phenyl or phenyl C₁₋₅ alkyl;-   if Ar¹ is (ii) then:-   R^(1′) is chosen from H, C₁₋₆ alkyl, C₁₋₅ alkylS(O)_(m)—, C₁₋₅    alkoxyl C₁₋₅ alkylthiol, NH₂—C(O)—(CH₂)_(n)—, heterocycle,    heterocycleC₁₋₆ alkyl, heteroaryl and nitrile, each of the    aforementioned where possible are optionally partially or fully    halogenated or are optionally further substituted with    alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,    hydroxyl, oxo, nitro and nitrile;-   R^(2′) is chosen from C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl    and C₁₋₅ alkoxy;-   or if Ar¹ is (iii) then:-   ring d is a 5-6 membered heterocyclic ring.

In another embodiment, there are provided compounds of the formula (I)as described immediately above and wherein

-   if Ar¹ is (i) then:-   R¹ is chosen from hydrogen, C₁₋₆ alkyl or nitrile;-   R² is chosen from hydrogen, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, oxo or    C₁₋₅ alkylS(O)_(m)—;-   if Ar¹ is (ii) then:-   R^(1′) is chosen from hydrogen, C₁₋₆ alkyl, C₁₋₅ alkylS(O)_(m)—,    C₁₋₅ alkoxyl C₁₋₅ alkylthiol, NH₂—C(O)—(CH₂)_(n)—, morpholino C₁₋₆    alkyl, heteroaryl chosen from pyrazole, triazole, imidazole and    tetrazole, and nitrile;-   R^(2′) is chosen from C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl    and C₁₋₅ alkoxy;-   or if Ar¹ is (iii) then:-   ring d is a 5-6 membered heterocyclic ring such that rings c and d    fuse to form the following:    -   where each R is independently H or C₁₋₃ alkyl.

In yet another embodiment, there are provided compounds of the formula(I) as described in any of the embodiments shown above and wherein

-   J is chosen from C₁₋₁₀ alkyl, aryl and C₃₋₇ cycloalkyl each    optionally substituted by R^(b);-   R^(x) is independently chosen from C₁₋₆ alkyl which may optionally    be partially or fully halogenated, C₃₋₆ cycloalkyl optionally    substituted by C₁₋₃ alkyl and optionally partially or fully    halogenated, acetyl, aroyl, C₁₋₄ alkoxy, which may optionally be    partially or fully halogenated, halogen, methoxycarbonyl,    phenylsulfonyl and —SO₂—CF₃;-   R^(b) is chosen from hydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅    alkynyl, C₃₋₈ cycloalkylC₀₋₂ alkyl, aryl, C₁₋₅ alkoxy, C₁₋₅    alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅ dialkylamino, C₁₋₅ acyl,    C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₁₋₅    sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile,-   or R^(b) is chosen from heterocycle chosen from pyrrolidinyl,    pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,    thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,    tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,    1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,    tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene    sulfoxide, pentamethylene sulfone, tetramethylene sulfide,    tetramethylene sulfoxide and tetramethylene sulfone and heteroaryl    chosen from aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl,    thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,    imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl,    quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,    benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl,    triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,    pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,    oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl; and-   R⁷ is hydrogen.

In another embodiment, there are provided compounds of the formula (I)as described immediately above and wherein

-   Y is —O—, —S—, —NH—, —N(CH₂CH₃)— or —N(CH₃)—;-   X is —N(R^(a))- or —O—;-   Q is CH;-   each R³, R⁴ and R⁵ are hydrogen;-   R^(b) is chosen from hydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅    alkynyl, C₃₋₈ cycloalkylC₀₋₂ alkyl, aryl, C₁₋₅ alkoxy, C₁₋₅    alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅ dialkylamino, C₁₋₅ acyl,    C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₁₋₅    sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile-   or R^(b) is chosen from; heterocycle chosen from pyrrolidinyl,    pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,    thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,    tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,    1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,    tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene    sulfoxide, pentamethylene sulfone, tetramethylene sulfide,    tetramethylene sulfoxide and tetramethylene sulfone and heteroaryl    chosen from aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl,    thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,    imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl,    quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,    benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl,    triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,    pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,    oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   Y is —O—, —S— or —N(CH₃)—;-   R⁶ is present, and is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or    unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected from    morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl and    tetrahydrofuranyl, or aryl chosen from phenyl and naphthyl, each    alkyl, alkenyl, heterocycle and aryl are optionally substituted by    one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl    amino, amino or C₁₋₅ alkoxycarbonyl;    wherein each R⁶ is further optionally covalently attached to groups    chosen from:    -   hydrogen, NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy,        C₁₋₃ alkoxy, phenoxy, benzyloxy, phenylC₀₋₄ alkyl,        piperazinylC₀₋₄ alkyl, piperidinyl C₀₋₄alkyl, pyrrolidinylC₀₋₄        alkyl, morpholinylC₀₋₄ alkyl, tetrahydrofuranylC₀₋₄ alkyl,        triazolyl C₀₋₄alkyl, imidazolyl C₀₋₄alkyl and pyridinyl        C₀₋₄alkyl, each abovelisted heterocycle, heteroaryl and phenyl        group is optionally substituted by one to three hydroxy, oxo,        C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, —NR⁷R⁸,        NR⁷R⁸—C(O)— or C₁₋₄ acyl;        each R⁷ and R⁸ are independently hydrogen, phenylC₀₋₃alkyl        optionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl        amino, or R⁷ and R⁸ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or        unbranched alkyl optionally substituted by C₁₋₄ alkoxy, hydroxy        or mono or diC₁₋₃ alkyl amino.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   X is —O—;-   Y is —N(CH₃)—;-   R⁶ is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or    unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected from    morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl,    each alkyl, alkenyl, heterocycle and phenyl are optionally    substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono    or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl;    wherein each R⁶ is further optionally covalently attached to groups    chosen from:    -   hydrogen, —NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl,        benzyloxy, phenylC₀₋₄ alkyl, piperazinylC₀₋₄ alkyl, piperidinyl        C₀₋₄alkyl, pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄ alkyl,        triazolyl C₀₋₄alkyl, imidazolyl C₀₋₄alkyl and pyridinyl        C₀₋₄alkyl, each above-listed heterocycle, heteroaryl and phenyl        group is optionally substituted by one to three hydroxy, oxo,        C₁₋₄alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, amino, NR⁷R⁸—C(O)—        or C₁₋₄ acyl;        each R⁷ and R⁸ are independently hydrogen, phenylC₀₋₂alkyl        optionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl        amino, or R⁷ and R⁸ are C₁₋₅ branched or unbranched alkyl        optionally substituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃        alkyl amino;        R^(b) is chosen from hydrogen, C₁₋₅ alkyl, C₃₋₇ cycloalkylC₀₋₂        alkyl, aryl, C₁₋₅ alkoxy, amino, C₁₋₅ alkylamino, C₁₋₃        dialkylamino, C₁₋₃ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ acyloxy, C₁₋₃        acylamino, C₁₋₃ sulphonylamino, hydroxy, halogen,        trifluoromethyl, nitro, nitrile; or R^(b) is chosen from        pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl,        thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl,        piperazinyl, piperidinonyl, tetrahydropyrimidonyl, aziridinyl,        isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl,        pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl,        pyrazinyl and pyridazinyl.

In yet still another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

-   R⁶ is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or    unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected from    morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl,    each alkyl, alkenyl, heterocycle and phenyl are optionally    substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono    or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl;    wherein each R⁶ is further optionally covalently attached to groups    chosen from:    -   hydrogen, —NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl,        benzyloxy, phenylC₀₋₄ alkyl, piperazinyl, piperazinylC₁₋₂ alkyl,        piperidinyl, piperidinyl C₁₋₂alkyl, pyrrolidinyl, pyrrolidinyl        C₁₋₂ alkyl, morpholinyl, morpholinylC₁₋₂ alkyl, triazolyl,        triazolyl C₁₋₂alkyl, imidazolyl, imidazolyl C₁₋₂alkyl, pyridinyl        and pyridinyl C₁₋₂alkyl, each above-listed heterocycle,        heteroaryl and phenyl group is optionally substituted by one to        three hydroxy, oxo, C₁₋₄alkyl, C₁₋₃alkoxy, C₁₋₅alkoxycarbonyl,        amino, NR⁷R⁸—C(O)— or C₁₋₄ acyl.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R^(b) is chosen from hydrogen, C₁₋₅ alkyl, C³⁻⁶ cycloalkylC₀₋₂    alkyl, phenyl, C₁₋₅ alkoxy, amino, C₁₋₅ alkylamino, C₁₋₃    dialkylamino, C₁₋₃ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ acyloxy, C₁₋₃    acylamino, hydroxy, halogen;-   or R^(b) is chosen from morpholinyl, thiomorpholinyl,    thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl,    piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R^(b) is chosen from amino, C₁₋₅ alkylamino, C₁₋₃ dialkylamino;-   or R^(b) is chosen morpholinyl, piperidinyl and pyridinyl.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   Rx is chosen from:

For any of the above described embodiments, preferred embodiments whereAr¹ is (i) and includes:

For any of the above described embodiments, preferred embodiments whereAr¹ is (ii) include:

where R in these structures is C₁₋₅alkyl.

The following are representative compounds of the invention: TABLE I

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(2-tert-butyl-5-methoxy-pyridin-4-yl)- amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid(5-tert-butyl-2- methanesulfinyl-phenyl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid(5-tert-butyl-2- methanesulfonyl-phenyl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid(5-tert-butyl-2-oxo-1,2- dihydro-pyridin-3-yl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid(5-tert-butyl-1-methyl-2-oxo- 1,2-dihydro-pyridin-3-yl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid(5-tert-butyl-2-methyl-pyridin- 3-yl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid(5-tert-butyl-3-cyano-2- methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-2-methyl-pyridin-3-yl)- amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-3-cyano-2-methoxy-phenyl)- amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfinyl-phenyl)- amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-2-methyl-pyridin-3-yl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)pyridin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfinyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid(5-tert-butyl-3-cyano-2-methoxy-phenyl)- amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid(2-tert-butyl-5-methanesulfinyl-pyridin-4-yl)- amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid[5-tert-butyl-2-methoxy-3-(2- oxo-pyrrolidin-1-yl)-phenyl]-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2- carboxylic acid[5-tert-butyl-2-methoxy-3-(2- oxo-azetidin-1-yl)-phenyl]-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid(2-amino-6-tert-butyl-3-methoxy-pyridin-4- yl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylic acid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-(pyridin-4-yloxy]-1H-indole-2-carboxylic acid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide or the pharmaceutically acceptablesalts and/or isomers thereof.

In all the compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

Of particular importance according to the invention are compounds offormula (I), for use as pharmaceutical compositions with ananti-cytokine activity.

The invention also relates to the use of a compound of formula (I), forpreparing a pharmaceutical composition for the treatment and/orprevention of a cytokine mediated disease or condition.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of formula (I), or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. Isomers shall be defined as being enantiomersand diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods using all suchtautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groupsshall be understood as being branched or unbranched where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic either aromaticor non-aromatic ring systems. The non-aromatic ring systems may be mono-or polyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinterchangeably.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Unless otherwise stated,heterocycles include but are not limited to, for example pyrrolidinyl,pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide,pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxideand tetramethylene sulfone.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N, O and S. Unless otherwise stated, suchheteroaryls include aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl,indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl,quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl,pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl,pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl andimidazo[4,5-b]pyridinyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in defintions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein. Each aryl or heteroarylunless otherwise specified includes it's partially or fully hydrogenatedderivative. For example, quinolinyl may include decahydroquinolinyl andtetrahydroquinolinyl, naphthyl may include it's hydrogenated derivativessuch as tetrahydranaphthyl. Other partially or fully hydrogenatedderivatives of the aryl and heteroaryl compounds described herein willbe apparent to one of ordinary skill in the art.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. Forexample, for an —S—C₁₋₆ alkyl radical, unless otherwise specified, thisshall be understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “partially or fully halogenated”; partially orfully fluorinated; “substituted by one or more halogen atoms”, includesfor example, mono, di or tri halo derivatives on one or more carbonatoms. For alkyl, a nonlimiting example would be —CH₂CHF₂, —CF₃ etc.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

General Synthetic Methods

The invention additionally provides for methods of making the compoundsof the formula (I). The compounds of the invention may be prepared bythe general methods and examples presented below, and methods known tothose of ordinary skill in the art. Further reference in this regard maybe made to U.S. Pat. No. 6,358,945, U.S. application Ser. Nos.09/714,539, 09/834,797, 10/120,028, 10/143,322 and 10/147,675. U.S.application Ser. No. 10/264,689 teaches additional methods forpreparation of sulfonamide intermediates. Each of the aforementioned UScases are incorporated in their entirety.

In all schemes, unless otherwise specified, Ar¹, X, Y, W and R³-R⁶ inthe formulas shown below shall have the meanings defined for thesegroups in the definition of the formula (D) of the invention, describedhereinabove. Intermediates used in the syntheses below are eithercommercially available or easily prepared by methods known to thoseskilled in the art. Reaction progress may be monitored by conventionalmethods such as thin layer chromatography (TLC). Intermediates andproducts may be purified by methods known in the art, including columnchromatography, HPLC or recrystallization.

Compounds of the invention where Q is a carbon atom, may be prepared asdescribed in Schemes I and II. Compounds of the invention wherein Q is anitrogen atom, may be prepared by analogous methods which will beapparent to one of ordinary skill in the art.

As illustrated in Scheme I an amine bearing Ar¹ is coupled withcarboxylic acid III, where P is a protecting group, using standardcoupling conditions known in the art (see for example M. Bodanszky,1984, The Practice of Peptide Synthesis, Springer-Verlag). For example,one may couple III and II by treating with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)followed by 1-hydroxybenzotriazole hydrate (HOBT) in a suitable solventsuch as DMF. Removal of the protecting group P to provide V may beachieved by standard procedures known in the art. For example, if P is abenzyl group, it may be removed by treatment of IV with hydrogen gas inthe presence of a catalyst such as palladium on carbon in a suitablesolvent such as EtOH. The resulting intermediate V may then be coupledwith the desired halo heterocycle VI (Z=halogen) bearing R⁶ in thepresence of a suitable base to provide I. Ar¹ and R⁶ may be furthermodified by standard synthetic methods known in the art to produceadditional compounds of formula (I). Several examples are described inthe Synthetic Examples section below.

In a modification of the above method, the order of coupling VI andAr¹NH₂ with the central heterocycle may be reversed. This is illustratedin Scheme II.

As illustrated above, the ester VII (R=lower alkyl such as methyl orethyl, P=a protecting group) is deprotected as described above and theresulting intermediate VIII is coupled, as described above to provideester IX. This is hydrolyzed using standard hydrolysis conditions andthe resulting acid coupled with Ar¹NH₂ to provide I. As above, Ar¹ andR⁶ may be further modified by standard synthetic methods known in theart to produce additional compounds of formula (I). Several examples aredescribed in the Synthetic Examples section below.

SYNTHETIC EXAMPLES Example 11-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

For a similar procedure to form the indole core, see R. Albrecht et al.Eur. J. Med. Chem. Chim. Ther. 1985, 20, 59-60.

Preparation of 1-Benzyloxy-3-methyl-2-nitro-benzene (Compound 2)

To a mechanically stirred solution of 1 (760 g, 4.96 mol) inacetonitrile (12.1 L) was added potassium carbonate (857 g, 6.2 mol).Benzyl bromide (590 mL, 4.96 mol) was added to the dark red suspensionover 5 h which raised the temperature slightly. The reaction was heatedto 75° C. over 45 min and then held at 75° C. for 2 h over which timethe reaction turned orange. The reaction was allowed to cool to 40° C.and water (6.2 L) was added. The reaction was transferred to aseparatory funnel and the reaction flask washed with ethyl acetate (1 L)to complete the transfer. The layers were separated and the aqueouslayer extracted with ethyl acetate (6 L). The combined organics werewashed with brine (5 L) and then dried over sodium sulfate. The mixturewas filtered through celite and concentrated to an orange oil. The oilwas redissolved in ethyl acetate and filtered through celite a secondtime to remove residual solids. The solution was then concentrated anddried under vacuum to give 2 (1199 g, 99%) as an orange oil.

Preparation of 3-(3-Benzyloxy-2-nitro-phenyl)-2-hydroxy-acrylic acidethyl ester potassium salt (Compound 3)

To a stirred solution of MTBE (16 L) was added a 1 M solution ofpotassium t-butoxide in THF (4.9 L, 4.9 mol). Diethyl oxalate (667 mL,4.9 mol) was added via addition funnel causing a slight exotherm. Asolution of 2 (1199 g, 4.9 mol) in MTBE (2 L) was added over 1 h. Thereaction was stirred at room temperature for 3 h and then heated atreflux overnight. The reaction was allowed to cool to room temperatureand the solids were collected by vacuum filtration, washed with MTBE,and dried under vacuum to give compound 3 as an orange solid (1398 g,74%).

Preparation of 7-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester(Compound 4)

A suspension of iron powder (2783 g, 50 mol) in acetic acid (12.3 L) washeated to 50° C. A solution of 3 (1422 g, 3.72 mol) in acetic acid (4.2L) was added over 3.5 h in an exothermic reaction. The reaction washeated at 80° C. for 12 h. The reaction was cooled to 50° C. and ethylacetate (16 L) was added and the suspension stirred for 0.5 h. Thesuspension was filtered through celite and washed through with ethylacetate (8 L). The filtrate was concentrated to a brown paste. The pastewas redissolved in ethyl acetate (16 L) and a 0.4 M solution oftetrasodium EDTA (16 L) was added. The solution was saturated with solidsodium bicarbonate and stirred overnight. The layers were separated andthe aqueous layer extracted with ethyl acetate (4 L). The combinedorganics were washed with saturated sodium bicarbonate (2×7 L) and thenwashed with a 0.4 M solution of tetrasodium EDTA (7 L). The organicswere dried over sodium sulfate for 5 h and then filtered through a padof silica gel washing through with ethyl acetate. The filtrate wasconcentrated to give compound 4 (905 g, 82%) as a dark brown solid.

Preparation of 7-Benzyloxy-1-methyl-1H-indole-2-carboxylic acid ethylester (Compound 5)

A suspension of sodium hydride (132 g, 3.43 mol, 60% dispersion inmineral oil) was cooled to 10° C. in an ice bath. A solution of 4 (844g, 2.86 mol) in DMF (1.9 L) was added over 4.5 h with a slight exothermraising the temperature to 13° C. The reaction was stirred for anadditional 0.5 h. Methyl iodide (180 mL, 2.86 mol) was added over 1 hraising the temperature from 12.6° C. to 18.8° C. The reaction wasstirred overnight under nitrogen. The reaction was quenched withsaturated ammonium chloride (700 mL) causing a tan precipitate and anexotherm. Water (3 L) was added and the solids were collected by vacuumfiltration and washed with water (2 L). The solids (−1.5 kg) weredissolved in ethyl acetate (4 L) and washed with brine (1 L). The ethylacetate solution was treated with sodium sulfate and charcoal for 1 h.The mixture was filtered through celite and concentrated to a brownsolid. The solid (964 g) was mostly dissolved in 2% ethyl acetate inhepatane (4.8 L), decanted from the oily residue, and the solution wasfiltered and concentrated a dark yellow solid. The oily residue wasdissolved in ethyl acetate (5 volumes) and diluted with heptane (5volumes based on ethyl acetate) and the resulting precipitate collectedby vacuum filtration. The solids were combined and slurried with heptane(3 volumes), filtered, and dried under vacuum for 2 days to givecompound 5 (686 g, 76%) as a tan powder: mp 59-61° C.

Preparation of 7 7-Hydroxy-1-methyl-1H-indole-2-carboxylic acid ethylester (Compound 6)

5 (82.2 g, 266 mmol) and Pearlman's catalyst (2.0 g; 20% Pd(OH)₂/C, wet,Aldrich) were suspended in EtOH (300 mL) in a Parr Shaker jar. The jarwas purged with H₂ and shaken at RT (Parr shaker) under a constant 10psi of H₂ for 5 h. The final solution was filtered through Celite 545and concentrated to give the product (58.15 g; 99%) as an analyticallypure, off-white solid.

Preparation of7-(2-Chloro-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid ethylester (Compound 7)

The indole substrate (135.0 g, 602 mmol) and 2-chloro-4-iodopyridine(147 g, 614 mmol) were dissolved in anhydrous DMF (150 mL) under anatmosphere of N₂. DBU 144 mL, 963 mmol) was added in one portion. Thereaction was stirred at 110° C. for 16 hours, then cooled andconcentrated under high vacuum. The dark residue was taken up in EtOAc(1500 ml) and washed successively with 50% brine (300 mL), 5% aqueouscitric acid (2×300 mL), saturated aqueous sodium bicarbonate (2×300 mL),and brine (300 ml). The organic layer was dried over MgSO₄/decolorizingcharcoal, filtered, and concentrated to give a dark red-purple solid.Recrystallization from MeCN (260 mL) gave the product as pale purplecrystals (199 g, 67%).

Preparation of7-(2-Chloro-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(Compound 8)

The ester (53.2 g, 161 mmol) was dissolved in 1:1 THF/EtOH (1000 mL). 1Maqueous NaOH (370 mL, 370 mmol) was added over 30 minutes with vigorousstirring. The solution was stirred at RT for 5 hours. Water (500 mL) wasthen added, and the bulk of the organic solvents removed by rotaryevaporation (60° C.). The resulting aqueous solution was washed withEt₂O (2×200 mL) and the organic extracts discarded. The dark aqueoussolution was acidified to pH 5.2 (pH meter) with 10% HCl and thenextracted with EtOAc (4×400 mL). The combined organic extracts werewashed with brine (300 mL), dried over MgSO₄, filtered, andconcentrated. The residue was dissolved in the minimum amount of hotacetonitrile and decolorizing carbon added. The solution was refluxedfor 5 minutes, and then filtered through a pad of Celite which wassubsequently washed with hot acetonitrile (2×100 mL). The productcrystallized on cooling and was collected by filtration giving thedesired acid as an off-white, analytically pure solid (46 g, 95%).

Preparation of1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (Compound 9)

Flush with N₂ a 3-neck 250 mL round bottom flask equipped with anoverhead stirrer, reflux condensor, thermocouple thermometer, heatingmantle and N₂ line.

Charge 8 (6 g, 19 mmol) into the flask followed by t-BuONa (69 mmol) andtoluene (99 mL). Charge piperazine (39.6 mmol) into the flask. A mildexotherm brings the internal temperature to 30° C. Purge the solution bysparging with N₂ 5-10 min.

Charge Xantphos (69 mmol) followed by Pd (0.3 mmol). Purge the mixtureagain by sparging with N₂ for 5-10 min. Heat the mixture to 95-100° C.and stir under N₂ for 4 h. Cool the mixture to 22-25° C. and add water(60 mL). Stir for 2-5 min and set aside the aqueous portion. Extract theorganic portion with 0.3 M NaOH (35 mL). The combined aqueous portionswere filtered through a pad of Darco G-60 charcoal and celite. The padwas filtered with 2 mL 0.3 M NaOH. Place the combined aqueous portionsover a bath at 20-25° C. and neutralize the solution to pH=6-7 with 2NHCl. The solution is stirred for 20 min to 30 min the solid by iscollected by filtration. The cake is rinsed with MTBE (20 mL) andair-dried overnight. The solid is dried by azeotropic distillation of aslurry with THF (3×75 mL) and then in a vacuum oven at 50° C. for aminimum of 6 h to afford 7.83 g (87%) of an off-white solid.

Preparation of1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide(Compound 10)

Charge 9 (6.0 g, 16.4 mmol) into a flask followed by THF (96.0 mL) andDMF (0.05 mL). Add oxalyl chloride (1.5 mL) slowly keeping the internaltemperature at 20-25° C. Stir for approx. 1.5 h. Aniline (18 mmol) andDMAP (catalytic) were added in one portion followed by Et₃N (2.65 mL).The mixture is stirred at ambient temperature for 2 hours.

The mixture was quenched with 5% NaHCO₃ (70 mL) and stirred for 10 min.The organic portion was removed and the aqueous was extracted with ethylacetate (1×70 mL) and MeTHF (1×70 mL). The combined organic portionswere washed with 5% NaCl (70 mL), dried (Na₂SO₄) and concentrated underreduced pressure to afford a brown oil. The resulting oil was dissolvedin acetonitrile (55.0 mL) at 55° C., allowed to reach 25-30° C. andfiltered. The cake was rinsed with 5 mL acetonitrile.

The mixture was then concentrated to an oil (approx. 30-40% by weight),diluted with acetonitrile at 50° C. The resulting solid was collected byfiltration. The cake was washed with acetonitrile (2×12 mL) and airdried for 1 h. The product was dried in a vacuum over at 50° to afford3.52 g (34.7%) of an off-white solid.

Example 2 Synthesis of1-methyl-7-[2-(4-methyl-piperizin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (2-tert-butyl-5-methoxy-pyidin-4-yl)-amide

To a solution of 2-tert-butyl-5-hydroxy-isonicotinonitrile (10.0 g, 73.5mmol) in acetonitrile/methanol (9:1, 20 mL) was addedN,N-diisopropylethylamine (1.48 mL, 8.52 mmol) followed by(trimethylsilyl)diazomethane (2.0M in hexane, 4.30 mL, 8.52 mmol). Thered solution was stirred for 18 h at room temperature and thenconcentrated in vacuo. The residue was dissolved in methylene chloride,washed with saturated aqueous NaHCO₃ dried over sodium sulfate,filtered, and concentrated in vacuo to provide2-tert-butyl-5-methoxy-isonicotinonitrile (1.10 g, 99%) as a pale yellowoil which was utilized without further purification.

The above nitrile (1.10 g, 5.68 mmol) was dissolved in aqueous sulfuricacid (9.0 M in water, 6.0 mL) and heated to 120° C. for 8 h. Thesolution was cooled to room temperature and NaOH (˜2.0 g) was addedslowly to neutralize the solution. The mixture was then diluted with anequal volume of saturated aqueous KH₂PO₄ and extracted several timeswith 25% 2-propanol in chloroform. The extracts were combined, driedover sodium sulfate, filtered, and concentrated in vacuo to provide2-tert-butyl-5-methoxy-isonicotinic acid (1.09 g, 92%) as a pale brownsolid which was utilized without further purification.

Ethyl chloroformate (101 microL, 1.05 mmol) was added dropwise to asolution of the above acid (200 mg, 0.96 mmol) andN,N-diisopropylethylamine (183 microL, 1.05 mmol) in acetone (1.0 mL) at0° C. The mixture was stirred for 0.5 h at 0° C. then warmed to roomtemperature and stirred an additional 0.5 h. Lastly, a solution ofsodium azide (5.0 M in water, 400 μL, 2.00 mmol) was added and theresultant slurry was stirred at room temperature for 1 h. Water wasadded to the reaction mixture and the aqueous phase was extracted withmethylene chloride. Toluene (2 mL) was added to the combined extractswhich were subsequently dried over sodium sulfate, filtered, andconcentrated in vacuo to a volume of 1 mL (Caution was taken to avoidcomplete concentration). The resultant toluene solution of the acylazide was then added dropwise to a refluxing solution of benzyl alcohol(120 microL, 1.15 mmol) in toluene (1 mL) and the mixture was refluxedan additional 1.5 h. Concentration in vacuo, followed by filtration ofthe residue through a plug of silica-gel with diethyl ether provided thecrude Cbz-protected aniline. This crude product was immediatelydissolved in ethanol/water (10:1, 3.0 mL) in a Parr hydrogenation vesseland Pd(OH)₂ (20% on carbon, 20 mg) was added. The reaction was placedunder a hydrogen atmosphere (50 psi) and shaken at room temperature for0.25 h. The solution was then filtered through diatomaceous earth,concentrated and the residue was purified by silica-gel chromatography(ethyl acetate) to provide 2-tert-butyl-5-methoxy-pyridin-4-ylamine (95mg, 56%) as a white solid.

To a slurry of 7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (163 mg,0.58 mmol) in methylene chloride (2 mL) at 0° C. was added oxalylchloride (72 microL, 0.84 mmol) followed by a drop ofN,N-dimethylformamide. The solution immediately bubbled and became clearafter a period of 0.75 h. The mixture was concentrated and redissolvedin methylene chloride (1.5 mL). The acid chloride solution was added toa solution of N,N-diisopropylethylamine (202 microL, 1.16 mmol) and2-tert-butyl-5-methoxy-pyridin-4-ylamine (95 mg, 0.52 mmol) in methylenechloride (1.5 mL). The solution was stirred at room temperature for 3 hthen poured onto saturated aqueous NaHCO₃. The aqueous layer wasextracted with methylene chloride and the combined extracts were washedwith saturated aqueous NaHCO₃, followed by saturated aqueous KH₂PO₄, andagain with saturated aqueous NaHCO₃. The organic extracts were driedover sodium sulfate, filtered through a plug of silica-gel with diethylether, and concentrated in vacuo to provide pure7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid(2-tert-butyl-5-methoxy-pyidin-4-yl)-amide (231 mg, 99%) as a whitesolid.

Pd(OH)₂ (20% on C, 24 mg) was added to a solution of the above indole(231 mg, 0.52 mmol) in ethanol/ethyl acetate (3:2, 5.0 mL) at roomtemperature. The solution was placed under a hydrogen atmosphere (1 atm)and stirred at room temperature for 18 h. The mixture was filteredthrough diatomaceous earth and concentrated in vacuo to provide7-hydroxy-1-methyl-1H-indole-2-carboxylic acid(2-tert-butyl-5-methoxy-pyidin-4-yl)-amide (199 mg, 99%) as a pale brownsolid.

A solution of the above indole amide (93 mg, 0.26 mmol) and DBU (40micro L, 0.26 mmol) in acetonitrile (1.0 mL) was added dropwise to aslurry of 2,4-dichloropyrimidine (39 mg, 0.26 mmol) in acetonitrile (1.0mL). The solution was stirred for 18 h at 30° C. and an additionalequivalent of DBU (40 microL, 0.26 mmol) was added to the solution,followed by 1-methylpiperizine (146 microL, 1.32 mmol). The mixture washeated to 60° C. for 1 h then concentrated in vacuo. The residue waspartitioned between saturated aqueous NaHCO₃ and methylene chloride. Theaqueous layer was extracted with methylene chloride. The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by semi-prep HPLC toprovide the title compound, (22 mg, 16%) as a white solid (·3TFA salt):mp: 72-74° C. (dec.); ESI MS m/z 530 [C₂₉H₃₅N₇O₃+H]⁺; HPLC>95%,t_(R)=13.68 min.

Example 3 Synthesis of1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfinyl-phenyl)-amide

Triflic anhydride (4.14 mL, 24.6 mmol) was added dropwise to a solutionof 4-tert-butyl-2-nitrophenol (4.00 g, 20.5 mmol) and pyridine (2.16 mL,26.7 mmol) in methylene chloride (50 mL) at 0° C. The yellow solutionwas stirred 0.25 h at 0° C., poured onto saturated aqueous NaHCO₃ andextracted with methylene chloride. The combined extracts were washedwith saturated aqueous NaHCO₃, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by filtration through aplug of silica-gel (methylene chloride) to providetrifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (5.82g, 87%) as a pale yellow oil which was utilized without furtherpurification.

Sodium thiomethoxide (1.86 g, 26.6 mmol) was added to a cooled solutionof the above triflate (5.80 g, 17.7 mmol) in DMF (35 mL) at 0° C. Thered solution was warmed to room temperature and stirred at thattemperature for 0.75 h, poured onto saturated aqueous NaHCO₃ and theaqueous layer was extracted with hexane. The combined extracts werewashed with saturated aqueous NaHCO₃, dried over sodium sulfate,filtered, and concentrated in vacuo to provide a mixture (1:1) of thedesired product and starting phenol. The residue was purifiedrecrystallization from hexane to provide a yellow precipitate which wasfiltered off and washed with hexane. The remaining filtrate wasconcentrated in vacuo and repurified by silica-gel chromatography (3%diethyl ether in hexanes). The purified products were combined toprovide 4-tert-butyl-1-methylsulfanyl-2-nitro-benzene (2.19 g, 55%) as abright yellow solid.

Sodium periodate (1.23 g, 5.76 mmol) in water (2.0 mL) was added to asolution of the above thioether (1.08 g, 4.80 mmol) in methanol/THF(2:1, 15 mL). The mixture was stirred at 50° C. for 24 h, then thesolvent was concentrated in vacuo. The residue was diluted with diethylether and washed with water and saturated aqueous NaHCO₃, dried oversodium sulfate, filtered, and concentrated in vacuo. Purification of thecrude product by silica-gel chromatography (methylene chloride—50% ethylacetate in methylene chloride) provided4-tert-butyl-1-methanesufinyl-2-nitro-benzene (1.05 g, 91%) as a whitesolid.

Tin(II)chloride dihydrate (2.84 g, 12.6 mmol) was added to a solution ofthe above sulfoxide (1.01 g, 4.19 mmol) in ethyl acetate (20 mL). Themixture was heated to reflux for 0.25 h upon which the solution becamered in color. The solution was cooled to room temperature and pouredonto aqueous 2.0 M NaOH. The aqueous phase was extracted with diethylether and the combined organic layers were washed with saturated aqueousNaHCO₃. The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo. The residue was redissolved indiethyl ether and extracted (3×) with 1.0 M HCl. The pH of the combinedaqueous layers was adjusted to pH=10 with NaHCO₃ and extracted withmethylene chloride. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo to provide5-tert-butyl-2-methanesufinyl-phenylamine (693 mg, 78%) as a whitesolid.

1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (127 mg, 0.473mmol) and HATU (180 mg, 0.473 mmol) were combined in DMF (900 microL)and stirred for 5 min at room temperature. The above aniline (100 mg,0.473 mmol) was added to the reaction mixture followed byN,N-diisopropylethylamine (247 microL, 1.42 mmol). The solution wasstirred at room temperature for 18 h then poured onto saturated aqueousNaHCO₃. The aqueous layer was extracted with methylene chloride and thecombined extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo. Purification by silica-gel chromatography(diethyl ether—1% methanol in diethyl ether) provided the titlecompound, in 92% purity. Trituration with diethyl ether provided pure1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfinyl-phenyl)-amide (63 mg, 33%) as a whitesolid, mp: 88-92° C. (dec.); ESI MS m/z 462 [C₂₆H₂₇N₃O₃S+H]⁺; HPLC>96%,t_(R)=15.89 min.

Example 4 Synthesis of1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfonyl-phenyl)-amide

3-Chloroperoxybenzoic acid (77%, 1.84 g, 10.6 mmol) was added to asolution of 4-tert-butyl-1-methylsulfanyl-2-nitro-benzene (800 mg, 3.55mmol) in methylene chloride (7.0 mL) at 0° C. The mixture was stirred atroom temperature for 5 h, diluted with diethyl ether and poured ontosaturated aqueous NaHCO₃. The organic layer was washed twice withsaturated aqueous NaHCO₃, twice with saturated aqueous Na₂CO₃, driedover sodium sulfate, filtered, and concentrated in vacuo. Purificationby silica-gel chromatography (20% ethyl acetate in hexane) provided4-tert-butyl-1-methanesulfonyl-2-nitro-benzene (781 mg, 86%) as a whitesolid.

Tin(II)chloride dihydrate (2.73 g, 12.1 mmol) was added to a solution ofthe above sulfone (777 mg, 3.02 mmol) in ethyl acetate (15 mL). Themixture was heated to reflux for 0.5 h then cooled to room temperatureand poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted withdiethyl ether and the combined organic layers were washed with saturatedaqueous NaHCO₃, dried over sodium sulfate, filtered and concentrated invacuo to provide pure 5-tert-butyl-2-methanesulfonyl-phenylamine (618mg, 90%) as a white solid.

1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (47 mg, 0.177mmol) and the above aniline (50 mg, 0.194 mmol) were dissolved inpyridine (600 microL) at room temperature. Phosphorus oxychloride (18micro L, 0.194 mmol) was added dropwise to the solution and the reactionmixture was stirred at room temperature for 0.5 h. The solvent wasconcentrated and the residue was partitioned between saturated aqueousNaHCO₃ and methylene chloride. The aqueous layer was extracted withmethylene chloride and the combined organic extracts were dried oversodium sulfate, filtered, and concentrated in vacuo. Purification bysilica-gel chromatography (1% methanol in diethyl ether) provided1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfonyl-phenyl)-amide (54 mg, 34%) as a whitesolid: mp: 158-159° C. (dec.); ESI MS m/z 478 [C₂₆H₂₇N₃O₄S+H]⁺;HPLC>97%, t_(R)=18.07 min.

Example 5 Synthesis of1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-oxo-1,2-dihydropyridin-3-yl)-amide

3-Nitro-5-tert-butyl-1H-pyidin-2-one (360 mg, 1.83 mmol) was dissolvedin methanol/ethyl acetate (2:1, 3 mL) and placed in a Parr hydrogenationvessel. Pd (10% on carbon, 36 mg) was added and the reaction was placedunder a hydrogen atmosphere (50 psi) and shaken at room temperature for2 h. The solution was then filtered through diatomaceous earth andconcentrated in vacuo. The residue was redissolved in diethyl ether andextracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers wasadjusted to 10 with NaHCO₃ and extracted with methylene chloride. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo to provide 3-amino-5-tert-butyl-1H-pyidin-2-one(195 mg, 64%) as a pale green solid: ESI MS m/z 166 [C₉H₁₄N₂O+H]⁺.

1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (145 mg, 0.542mmol) and HATU (206 mg, 0.542 mmol) were combined in DMF (1 mL) andstirred 5 min at room temperature. The above aminopyridinone (90 mg,0.542 mmol) was added to the reaction mixture followed byN,N-diisopropylethylamine (283 microL, 1.63 mmol). The solution wasstirred at room temperature for 72 h then poured into saturated aqueousNaHCO₃.

The aqueous layer was extracted with chloroform and the combinedextracts were dried over sodium sulfate, filtered, and concentrated invacuo. Purification by silica-gel chromatography (2% ammonium hydroxide,50% ethyl acetate in hexane) provided1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-oxo-1,2-dihydropyridin-3-yl)-amide (163 mg, 73%) as awhite solid: mp: 236-238° C. (dec.); ESI MS m/z 417 [C₂₄H₂₄N₄O₃+H]⁺;HPLC>97%, t_(R)=14.74 min.

Example 6 Synthesis of1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-amide

Ethyl nitroacetate (1.64 g, 12.3 mmol) was added to a solution ofmethylamine (33% in methanol, 7.7 mL, 61.6 mmol) and the solution wasstirred at room temperature for 18 h. The solvent was concentrated invacuo and the residue was dissolved in aqueous 1.0 M HCl. The aqueouslayer was washed with diethyl ether and the organic washings werediscarded. The aqueous layer was then extracted with ethyl acetate andthe combined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo to provide N-methyl-2-nitro-acetamide (961 mg,66%) as a pale yellow solid.

To a solution of 2-tert-butyl-malonaldehyde (385 mg, 3.00 mmol) and theabove amide (355 mg, 3.00 mmol) dissolved in ethanol (6.0 mL) was addedpyrrolidine (63 microL, 0.750 mmol). The mixture was heated at refluxfor 18 h and concentrated in vacuo. Purification by silica-gelchromatography (75% ethyl acetate in hexanes) provided5-tert-butyl-1-methyl-3-nitro-1H-pyridin-2-one (186 mg, 30%) as anorange solid.

The above nitro pyridine (186 mg, 0.886 mmol) was dissolved inmethanol/ethyl acetate (2:1, 3 mL) and placed in a Parr hydrogenationvessel. Pd (10% on carbon, 20 mg) was added and the reaction was placedunder a hydrogen atmosphere (50 psi) and shaken at room temperature for1 h. The solution was then filtered through diatomaceous earth andconcentrated in vacuo. The residue was redissolved in diethyl ether andextracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers wasadjusted to 10 with NaHCO₃ and extracted with methylene chloride. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo to provide3-amino-5-tert-butyl-1-methyl-1H-pyridin-2-one (110 mg, 69%) as a bluesolid: ¹ESI MS m/z 180 [C₁₀H₁₆N₂O₃+H]⁺.

1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (125 mg, 0.466mmol) and the above aminopyridinone (84 mg, 0.466 mmol) were dissolvedin pyridine (1.5 mL) at room temperature. Phosphorus oxychloride (48micro L, 0.513 mmol) was added dropwise to the solution and the reactionmixture was stirred at room temperature for 0.5 h. The solvent wasconcentrated in vacuo and the residue was partitioned between saturatedaqueous NaHCO₃ and methylene chloride. The aqueous layer was extractedwith methylene chloride and the combined organic extracts were driedover sodium sulfate, filtered, and concentrated in vacuo. Purificationby silica-gel chromatography (50% ethyl acetate in methylene chloride)provided 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-amide (65 mg, 33%)as a pale pink solid: mp: 74-76° C. (dec.); ESI MS m/z 431[C₂₅H₂₆N₄O₃+H]⁺; HPLC>97%, t_(R)=15.69 min.

Example 7 Synthesis of1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methyl-pyridin-3-yl)-amide

To a solution of 5-tert-butyl-2-chloro-3-nitro-pyridine (554 mg, 2.58mmol) dissolved in 10% aqueous dioxane (5.0 mL) was added potassiumcarbonate (1.07 g, 7.74 mmol), trimethylboroxine (395 mL, 2.84 mmol),and lastly tetrakis-(triphenylphosphine)palladium (149 mg, 0.129 mmol).The solution was heated in a sealed tube to 100° C. for 18 h, cooled toroom temperature and diluted with ether. The organic layer was washedtwice with saturated aqueous NaHCO₃, dried over sodium sulfate,filtered, and concentrated in vacuo. Purification by silica-gelchromatography (10% ethyl acetate in hexane) provided5-tert-butyl-2-methyl-3-nitro-pyridine (388 mg, 75%) as colorless oil.

The above pyridine (388 mg, 1.99 mmol) was dissolved in ethanol (6 mL)and placed in a Parr hydrogenation vessel. Pd (10% on carbon, 20 mg) wasadded and the reaction was placed under a hydrogen atmosphere (50 psi)and shaken at room temperature for 18 h. The solution was then filteredthrough diatomaceous earth, concentrated in vacuo to provide5-tert-butyl-2-methyl-pyidin-3-ylamine (340 mg, 99%) as a pale orangesolid: ESI MS m/z 164 [C₁₀H₁₆N₂+H]⁺.

1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (183 mg, 0.683mmol) and HATU (259 mg, 0.683 mmol) were combined in DMF (1.2 mL) andstirred 5 min at room temperature. The above aminopyridine (102 mg,0.621 mmol) was added to the reaction mixture followed byN,N-diisopropylethylamine (326 microL, 1.86 mmol). The solution wasstirred at room temperature for 18 h then poured onto saturated aqueousNaHCO₃. The aqueous layer was extracted with methylene chloride and thecombined extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo. Purification by silica-gel chromatography (1%ammonium hydroxide, 50% ethyl acetate in methylene chloride) provided1-methyl-7-(pyridine-4-yloxy)-H-indole-2-carboxylic acid(5-tert-butyl-2-methyl-pyridin-3-yl)-amide (163 mg, 63%) as a paleyellow solid: mp: 52-56° C. (dec.); ESI MS m/z 415 [C₂₅H₂₆N₄O₂+H]⁺;HPLC>95%, t_(R)=12.29 min.

Example 8 Synthesis of 3-Amino-5-tert-butyl-2-methoxy-benzonitrile

To a solution of 5-tert-butyl-2-hydroxybenzaldehyde (1.25 g, 7.0 mmol)in ethyl acetate (15 mL) was added (NO)+18-crown-6-H(NO₃)₂ (2.64 g, 6.3mmol). The solution turned yellow and was stirred at room temperaturefor 5 h. The solvent was evaporated, giving a residue which was taken upin ether. The ether was washed 4× with saturated NH₄Cl, dried overNa₂SO₄, filtered, and concentrated in vacuo to give5-tert-butyl-2-hydroxyl-3-nitro-benzaldehyde (1.56 g, 99%) as a yellowsolid.

The above aldehyde (1.4 g, 6.3 mmol), hydroxylamine hydrochloride (0.438g, 6.3 mmol), and sodium formate (0.771 g, 11.3 mmol) in formic acid (20mL) were heated overnight, at reflux, then cooled to room temperature.The reaction was diluted with water, and the resulting precipitate wasfiltered. The solid was taken up in ether, dried over Na₂SO₄, filteredand concentrated in vacuo to yield5-tert-butyl-2-hydroxyl-3-nitro-benzonitrile (1.21 g, 87%) as a yellowsolid.

The above nitrile (0.5 g, 2.27 mmol) was taken up in 1:9methanol/acetonitrile (20 mL). N,N-diisopropylethylamine (1.1 mL, 6.35mmol) was added dropwise followed by (trimethylsilyl)diazomethane (3.2mL, 6.35 mmol). The reaction was stirred until the bubbling stopped (20min) and the reaction was quenched with water. The water was extracted3× with methylene chloride, dried over Na₂SO₄, filtered, andconcentrated in vacuo to give5-tert-butyl-2-methoxy-3-nitro-benzonitrile (0.531 g, 99%) as a yellowsolid.

The above benzonitrile (100 mg, 0.427 mmol) was dissolved in 1:1 ethylacetate/methanol (10 mL) in a nitrogen-flushed flask. Ammonium formate(270 mg, 4.27 mmol) and palladium on carbon (30 mg, 10% wet) were addedand the mixture was heated to reflux for 30 min. The reaction was cooledto room temperature and filtered through a pad of diatomaceous earth,eluting with ethyl acetate. The ethyl acetate was evaporated undervacuum. The resulting residue was purified by chromatography on silicagel (1:1 ethyl acetate/hexanes) to afford the title compound, (67 mg,77%) as a colorless oil.

Example 9 Synthesis of 6-tert-butyl-3-methoxy-pyridine-2,4-diamine

2-tert-Butyl-5-ethoxy-oxazole (16.6 g, 98.1 mmol) was dissolved infreshly distilled ethyl acrylate (11.7 mL, 108 mmol). The solution washeated in a sealed tube to 100° C. for 24 h. Upon cooling, the remainingstarting materials were distilled away from the product which wasfurther purified by filtration through a plug of silica-gel (methylenechloride) and concentrated to provide2-tert-butyl-5-hydroxy-isonicotinic acid ethyl ester (11.2 g, 54%) as apale yellow oil.

To a solution of the above isonicotinic acid ethyl ester (2.0 g, 9.47mmol) in DMF (20 mL) was added N-bromosuccinimide (1.85 g, 10.4 mmol).The solution was stirred at room temperature for 0.5 h then poured intosaturated aqueous NaHCO₃. The aqueous layer was extracted with diethylether and the combined organic layers were washed with saturated aqueousNaHCO₃, dried over sodium sulfate, filtered, and concentrated in vacuoto provide 2-bromo-6-tert-butyl-3-hydroxy-isonicotinic acid ethyl ester(2.74 g, 96%) as a pale yellow oil which was utilized without furtherpurification.

To a solution of the above bromopyridine (2.74 g, 9.07 mmol) inacetonitrile/methanol (9:1, 33 mL) was added N,N-diisopropylethylamine(2.50 mL, 14.2 mmol) followed by (trimethylsilyl)diazomethane (2.0M inhexane, 7.0 mL, 14.2 mmol). The red solution was stirred 0.5 h at roomtemperature then concentrated in vacuo. The residue was dissolved inmethylene chloride, washed with saturated aqueous NaHCO₃, dried oversodium sulfate, filtered, and concentrated in vacuo to provide2-bromo-6-tert-butyl-3-methoxy-isonicotinic acid ethyl ester (2.65 g,93%) as a red oil which was utilized without further purification.

To a solution of the above bromide (2.65 g, 8.39 mmol) in DMF (18 mL)was added copper(I)cyanide (3.8 g, 42 mmol). The mixture was heated to100° C. for 18 h then cooled to room temperature. The resultant blacksolution was poured into saturated aqueous NaHCO₃ and the aqueous layerwas extracted with diethyl ether. The combined organic extracts werewashed with saturated aqueous NaHCO₃, dried over sodium sulfate,filtered through a plug of silica gel (methylene chloride), andconcentrated in vacuo to provide6-tert-butyl-2-cyano-3-methoxy-isonicotinic acid ethyl ester (1.55 g,70%) as a yellow oil which was utilized without further purification.

To a solution of the above nitrile (616 mg, 2.35 mmol) in ethanol (8.0mL) was added NaOH (2.0 M in water, 8.3 mL, 16.5 mmol). The mixture washeated to reflux for 20 h then cooled to room temperature and theethanol was concentrated in vacuo. The basic solution was neutralizedwith 12 N HCl to a pH=6 then extracted with chloroform/isopropanol(3:1). The combined organic extracts were dried over sodium sulfate,filtered, and concentrated in vacuo to provide6-tert-butyl-3-methoxy-pyridine-2,4-dicarboxylic acid (402 mg, 68%) as ayellow solid which was utilized without further purification.

To a solution of the above diacid (123 mg, 0.49 mmol) in methylenechloride/THF (3:1, 1.0 mL) was added oxalyl chloride (104 microL, 1.21mmol) followed by 1 drop of DMF. The solution initially bubbled and wasstirred at room temperature for 3 h, then concentrated in vacuo. Theresidue was dissolved in dry acetone (1.0 mL) and a solution of sodiumazide (2 M in water, 1.45 mL, 3.9 mmol) was added all at once. Themixture was immediately poured onto water and the aqueous layerextracted with methylene chloride. To the combined extracts was addedtoluene (4.0 mL) and the organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo to approximately 1 mL of tolueneremaining. An additional amount of toluene (5.0 mL) was added and thiswas again concentrated in vacuo to about 1.0 mL of toluene remaining.The resulting solution of diacyl azide was added dropwise to a refluxingsolution of benzyl alcohol (116 microL, 1.12 mmol) in toluene (1.0 mL)which immediately evolved nitrogen. After heating the solution at refluxfor 2 h, the mixture was cooled to room temperature and concentrated invacuo to provide(4-benzyloxycarbonylamino-6-tert-butyl-3-methoxy-pyridin-2-yl)-carbamicacid benzyl ester.

To a solution of the crude dicarbamate from above in ethanol (3.0 mL)was added Pd(OH)₂ (20% on carbon, 20 mg). The mixture was placed in aParr shaker and hydrogenated (50 psi) for 18 h. The solution wasfiltered and concentrated in vacuo. The resultant residue was purifiedby silica gel chromatography (1% concentrated ammonium hydroxide-5%methanol in chloroform) to provide the title compound, (43 mg, 45% over2 steps) as a white solid: ESI MS m/z 196 [C₁₀H₁₇N₃O+H]⁺.

Example 10 Synthesis of1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(2-oxo-azetidin-1-yl)-phenyl]-amide

2-Bromo-4-tert-butylanisole (4.54 g, 18.67 mmol) was dissolved in aceticanhydride (15 mL) and the solution was cooled to 0° C. A solution ofnitric acid (70%, 2.5 mL) in acetic anhydride (2.5 mL) was prepared bythe dropwise addition of HNO₃ (70%, 2.5 mL) to Ac₂O at 0° C. The HNO₃solution was pre-cooled to 0° C., and added dropwise to the stirredsolution of the 2-bromo-4-tert-butylanisole over 5 min. The mixture wasstirred at 0° C. for 1 h, then allowed to warm to room temperature andstirred overnight. The reaction mixture was diluted with EtOAc (150 mL)and saturated NaHCO₃ (50 mL) This mixture was then neutralized bygradual addition of solid NaHCO₃ until the pH was between 7-8. Theorganic layer was separated, washed with brine (50 mL) and dried overanhydrous Na₂SO₄. The solvents were removed in vacuo, the residue waspurified by column chromatography (eluting with 3:1 hexane-EtOAc) togive 2-bromo-4-tert-butyl-6-nitroanisole (2 g, 37%).

An oven-dried Schlenk tube was charged with the above nitroanisole (500mg, 1.74 mmol), 2-azetidinone (150 mg, 2.1 mmol),tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol) andcesium carbonate (795 mg, 2.44 mmol). The tube was capped with a rubberseptum, purged with argon and 1,4-dioxane (7 mL) was then added throughthe septum via a syringe. The tube was sealed with a teflon screwcap andthe reaction mixture was stirred at 100° C. for 20 h. The reactionmixture was cooled to room temperature, diluted with EtOAc (100 mL),washed with water, brine and dried over anhydrous Na₂SO₄. The solventwas removed in vacuo, and the crude product was purified by columnchromatography (2:1 hexane-EtOAc) to give1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-azetidin-2-one (516 mg,quantitative).

A mixture of the above coupled nitroanisole (250 mg, 0.90 mmol) and Pd(10% on carbon, 60 mg) in absolute EtOH (5 mL) was stirred under H₂ (1atm) overnight. The reaction mixture was filtered through diatomaceousearth, and solid residue was rinsed with EtOAc (20 mL). The filtrate wasconcentrated in vacuo to give1-(3-amino-5-tert-butyl-2-methoxy-phenyl)-azetidin-2-one (210 mg, 94%),which was used in next step without further purification.

To a suspension of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylicacid (40 mg, 0.15 mmol) in DMF (1 mL) was added Hunig's base (52 microL,0.3 mmol) resulting in a clear solution. After 5 min, HATU (90 mg, 0.23mmol) and HOAT (3 mg, 0.02 mmol) were added followed by the aboveanisidine (37 mg, 0.15 mmol). The mixture was stirred overnight. Thereaction mixture was diluted with EtOAc (30 mL), washed with water,brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by column chromatography (eluting with 30-80% EtOAcin hexane) to give the title compound (50 mg, 75%).

Example 11 Synthesis of1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide

An oven-dried Schienk tube was charged with2-bromo-4-tert-butyl-6-nitroanisole (500 mg, 1.74 mmol), 2-pyrrolidinone(158 μL, 2.09 mmol), Pd₂(dba)₃ (32 mg, 0.035 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol) andCs₂CO₃ (795 mg, 2.44 mmol). The tube was capped with a rubber septum,purged with argon and 1,4-dioxane (7 mL) was then added through theseptum via a syringe. The tube was sealed with a teflon screwcap, andthe reaction mixture was stirred at 100 C for 20 h. The reaction mixturewas cooled to room temperature, diluted with EtOAc (100 mL), washed withwater, brine and dried over anhydrous Na₂SO₄. The solvent was removed invacuo, and crude product was purified by column chromatography (2:1hexane-EtOAc) to give1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-pyrrolidin-2-one (150 mg,30%).

A mixture of the above coupled nitroanisole (145 mg, 0.50 mmol) and Pd(10% on carbon, 40 mg) in EtOAc (5 mL) was stirred under H₂ (1 atm)overnight. The reaction mixture was filtered through diatomaceous earthand solid residue was rinsed with EtOAc (20 mL). The filtrate wasconcentrated in vacuo to give1-(3-amino-5-tert-butyl-2-methoxy-phenyl)-pyrrolidin-2-one (100 mg,77%), which was used in the next step without further purification.

To a suspension of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylicacid (40 mg, 0.15 mmol) in DMF (1 mL) was added Hunig's base (52 microL,0.3 mmol) resulting in a clear solution. After 5 min, HATU (90 mg, 0.23mmol) and HOAT (3 mg, 0.02 mmol) were added followed by the aboveanisidine (39 mg, 0.15 mmol). The mixture was stirred overnight. Thereaction mixture was diluted with EtOAc (30 mL), washed with water,brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by column chromatography (eluting with 30-80% EtOAcin hexane) to give the title compound (60 mg, 78%).

Example 12 Synthesis ofN-[3-amino-2-methoxy-5-(1-methylcyclopropyl)-phenyl]-methanesulfonamide

To a solution of 4-hydroxyacetophenone (10.0 g, 73.5 mmol) in DMF (74mL) was added imidazole (12.0 g, 176.3 mmol) and tert-butyldimethylsilylchloride (13.3 g, 88.1 mmol). The colorless solution was stirred for0.75 h at room temperature then quenched with saturated aqueous NaHCO₃.The aqueous phase was extracted with hexanes and the combined organiclayers were washed with saturated aqueous NaHCO₃. The organic layerswere dried over sodium sulfate, filtered, and concentrated to providethe silyl ether (18.0 g, 98%) as a white solid which was utilizedwithout further purification.

Methyl(triphenylphosphonium) bromide (17.1 g, 48.0 mmol) was suspendedin THF (96 mL) and cooled to 0° C. n-Butyllithium (2.5 M in hexane, 19.2mL, 48.0 mmol) was added dropwise to the mixture. The red solution wasstirred at room temperature for 0.5 h. The acetophenone silyl ether(10.0 g, 40.0 mmol) from above was added. The solution turned brightyellow and a white precipitate formed. The mixture was stirred for 1 hat room temperature and then the solution was quenched with saturatedaqueous NaHCO₃. The aqueous phase was extracted with diethyl ether andthe combined organic layers were washed with saturated aqueous NaHCO₃.The organic layers were dried over sodium sulfate, filtered andconcentrated. The resulting mixture was eluted through a plug of silicagel (hexanes) and the filtrate was concentrated to provide the styrene(8.36 g, 84%) as a colorless oil.

Diethylzinc (1.0 M in hexanes, 69 mL, 69 mmol) was added to a solutionof the above styrene intermediate (6.85 g, 27.6 mmol) in dichloroethaneat 0° C. Diiodomethane (11.2 mL, 138 mmol) was then added dropwise tothe solution and the resulting mixture was stirred at 0° C. for 0.5 hand allowed to warm to room temperature for 2 h. The opaque mixture wasquenched with saturated aqueous NH₄Cl. The aqueous phase was extractedwith methylene chloride and the combined organic layers were washed withsaturated aqueous NaHCO₃. The organic layers were dried over sodiumsulfate, filtered through diatomaceous earth, and concentrated. Thecrude residue was dissolved in THF (50 mL) and TBAF (1.0 M in THF, 28mL, 28 mmol) was added at room temperature. The solution was stirred for2 h and then quenched with aqueous 1.0 M HCl. The aqueous phase wasextracted with EtOAc and the combined organic layers were washed withsaturated aqueous NaHCO₃. The organic layers were dried over sodiumsulfate, filtered and concentrated. Purification by silica-gelchromatography (1% 2-propanol/12% EtOAc in hexanes) provided the phenolintermediate (2.77 g, 68%) as a white solid:

(NO)18-crown-6.H(NO₃)₂ ¹ (18.0 g, 43.0 mmol) was added to a solution ofthe above phenol intermediate (2.77 g, 18.7 mmol) in EtOAc. The reactionmixture was heated to reflux for 5 min and then cooled to roomtemperature. The mixture was poured into aqueous 1.0 M HCl. The aqueousphase was extracted with diethyl ether. The combined organic layers weredried over sodium sulfate, filtered and concentrated. The residue wasdissolved in acetonitrile/MeOH (9:1, 62 mL), cooled to 0° C. andN,N-diisopropylethylamine (13 mL, 74.8 mmol) was added slowly. The deepred solution was warmed to room temperature andtrimethylsilyldiazomethane (2.0 M in hexane, 18.7 mL, 37.4 mmol) wasadded slowly to control nitrogen evolution. After stirring at roomtemperature for 0.5 h, the mixture was concentrated and partitionedbetween methylene chloride and saturated aqueous NH₄Cl. The aqueouslayer was extracted with methylene chloride and the combined extractswere dried over sodium sulfate, filtered and concentrated. Purificationby silica-gel chromatography (6% EtOAc in hexanes) provided thedinitroanisole (2.21 g, 47%) as a red oil.

Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to a solution ofthe above dinitroanisole (2.21 g, 8.76 mmol) in EtOAc (30 mL). Themixture was heated to reflux for 0.25 h upon which the solution becamered in color. The solution was cooled to room temperature and pouredinto aqueous 2.0 M NaOH. The aqueous phase was extracted with EtOAc andthe combined organic layers were washed with saturated aqueous NaHCO₃.The organic layers were dried over sodium sulfate, eluted through a plugof silica gel (1% ammonium hydroxide in methylene chloride), and thefiltrate was concentrated. The residue was dissolved in diethyl etherand extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layerswas adjusted to pH=12 with 2.0 M NaOH and extracted with methylenechloride. The combined organic layers were dried over sodium sulfate,filtered and concentrated to provide diaminoanisole (860 mg, 52%) as ared oil.

Triethylamine (521 μL, 3.74 mmol) was added to a solution of the abovediaminoanisole (718 mg, 3.74 mmol) in methylene chloride at −10° C.Methanesulfonyl chloride (290 μL, 3.74 mmol) was then added dropwiseover a 10 min period and the resulting solution was allowed to slowlywarm to room temperature over 2 h. The mixture was quenched withsaturated aqueous NaHCO₃ and the aqueous layer was extracted withmethylene chloride. The combined organic layers were dried over sodiumsulfate, filtered and concentrated. Purification by silica gelchromatography (1% ammonium hydroxide/35% EtOAc in hexanes to 1%ammonium hydroxide/50% EtOAc in hexanes) provided a red solid which wastriturated with diethyl ether/hexanes (1:1) to yield the title compound(510 mg, 51%) as a pale brown solid, mp 144-146° C.

This intermediate can then be coupled to the indole core and reactedfurther by the procedures described in the examples above, to formdesired analogous indole amides.

Methods of Use

In accordance with the invention, there are provided novel methods ofusing the compounds of the formula (I). The compounds disclosed thereineffectively block inflammatory cytokine production from cells. Theinhibition of cytokine production is an attractive means for preventingand treating a variety of cytokine mediated diseases or conditionsassociated with excess cytokine production, e.g., diseases andpathological conditions involving inflammation. Thus, the compounds areuseful for the treatment of diseases and conditions as described in theBackground section, including the following conditions and diseases:

-   osteoarthritis, atherosclerosis, contact dermatitis, bone resorption    diseases, reperfiision injury, asthma, multiple sclerosis,    Guillain-Barre syndrome, Crohn's disease, ulcerative colitis,    psoriasis, graft versus host disease, systemic lupus erythematosus    and insulin-dependent diabetes mellitus, rheumatoid arthritis, toxic    shock syndrome, Alzheimer's disease, diabetes, inflammatory bowel    diseases, acute and chronic pain as well as symptoms of inflammation    and cardiovascular disease, stroke, myocardial infarction, alone or    following thrombolytic therapy, thermal injury, adult respiratory    distress syndrome (ARDS), multiple organ injury secondary to trauma,    acute glomerulonephritis, dermatoses with acute inflammatory    components, acute purulent meningitis or other central nervous    system disorders, syndromes associated with hemodialysis,    leukopherisis, granulocyte transfusion associated syndromes, and    necrotizing entrerocolitis, complications including restenosis    following percutaneous transluminal coronary angioplasty, traumatic    arthritis, sepsis, chronic obstructive pulmonary disease and    congestive heart failure. The compounds of the invention may also be    useful for anticoagulant or fibrinolytic therapy (and the diseases    or conditions related to such therapy) as described in the U.S.    application Ser. No. 10/630,599.

The compounds of the invention are also p38 MAP kinase inhibitors.Activity can be demonstrated by using methods known in the art. See forexample Branger et al., (2002) J. Immunol. 168: 4070-4077, and the 46references cited therein, each incorporated herein by reference in theirentirety. As disclosed in the Background of the Invention, the compoundsof the invention will therefore be useful for treating inflammatory andoncological diseases. These diseases include but are not limited tosolid tumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma and mesothelioma.

Examples of brain cancers include, but are not limited to brain stem,optic and hypophtalmic glioma, cerebella and cerebral astrocytoma,medulloblastoma, ependymoma, as well as pituitary, neuroectodermal andpineal tumor.

Examples of peripheral nervous system tumors include, but are notlimited to neuroblastoma, ganglioneuroblastoma, and peripheral nervesheath tumors.

Examples of tumors of the endocrine and exocrine system include, but arenot limited to thyroid carcinoma, adrenocortical carcinoma,pheochromocytoma, and carcinoid tumors.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer.

Tumors of the female reproductive organs include, but are not limited toendometrial, cervical, ovarian, vaginal, and vulvar cancer, as well assarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),hepatoblastoma, cholangiocarcinoma (intrahepatic bile duct carcinoma),and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, Hodgkins lymphoma, cutaneous T-cell lymphoma,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, Ewings sarcoma, malignant fibrous histiocytoma,lymphosarcoma, angiosarcoma, and rhabdomyosarcoma. Leukemias include,but are not limited to acute myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia,and hairy cell leukemia.

Plasma cell dyscrasias include, but are not limited to multiple myeloma,and Waldenstrom's macroglobulinemia.

These disorders have been well characterized in man, but also exist witha similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

For therapeutic use, the compounds may be administered in anyconventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds may be administered alone or in combination with adjuvantsthat enhance stability of the inhibitors, facilitate administration ofpharmaceutic compositions containing them in certain embodiments,provide increased dissolution or dispersion, increase inhibitoryactivity, provide adjunct therapy, and the like, including other activeingredients. Advantageously, such combination therapies utilize lowerdosages of the conventional therapeutics, thus avoiding possibletoxicity and adverse side effects incurred when those agents are used asmonotherapies. The above described compounds may be physically combinedwith the conventional therapeutics or other adjuvants into a singlepharmaceutical composition. Reference is this regard may be made toCappola et al.: U.S. patent application Ser. No. 09/902,822, PCT/US01/21860 and U.S. application Ser. No. 10/214,782, each incorporated byreference herein in their entirety. Advantageously, the compounds maythen be administered together in a single dosage form. In someembodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formula (I) (w/w) or a combinationthereof. The optimum percentage (w/w) of a compound of the invention mayvary and is within the purview of those skilled in the art.Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

As mentioned above, dosage forms of the compounds described hereininclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. Referencein this regard may also be made to U.S. application Ser. No. 10/313,667.As the skilled artisan will appreciate, lower or higher doses may berequired depending on particular factors. For instance, specific dosageand treatment regimens will depend on factors such as the patient'sgeneral health profile, the severity and course of the patient'sdisorder or disposition thereto, and the judgment of the treatingphysician.

Biological Assays

Inhibition of TNF Production in THP Cells

The inhibition of cytokine production can be observed by measuringinhibition of TNFα in lipopolysaccharide stimulated THP cells (forexample, see W. Prichett et al., 1995, J Inflammation, 45, 97). Allcells and reagents were diluted in RPMI 1640 with phenol red andL-glutamine, supplemented with additional L-glutamine (total: 4 mM),penicillin and streptomycin (50 units/ml each) and fetal bovine serum(FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterileconditions; only test compound preparation was nonsterile. Initial stocksolutions were made in DMSO followed by dilution into RPMI 1640 2-foldhigher than the desired final assay concentration. Confluent THP.1 cells(2×10⁶ cells/ml, final conc.; American Type Culture Company, Rockville,Md.) were added to 96 well polypropylene round bottomed culture plates(Costar 3790; sterile) containing 125 μl test compound (2 foldconcentrated) or DMSO vehicle (controls, blanks). DMSO concentration didnot exceed 0.2% final. Cell mixture was allowed to preincubate for 30min, 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS; 1μg/ml final; Siga L-2630, from E. coli serotype 0111.B4; stored as 1mg/ml stock in endotoxin screened distilled H₂O at −80° C.). Blanks(unstimulated) received H₂O vehicle; final incubation volume was 250 μl.Overnight incubation (18-24 hr) proceeded as described above. Assay wasterminated by centrifuging plates 5 min, room temperature, 1600 rpm(400×g); supernatants were transferred to clean 96 well plates andstored −80° C. until analyzed for human TNFα by a commercially availableELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed bynon-linear regression (Hill equation) to generate a dose response curveusing SAS Software System (SAS institute, Inc., Cary, N.C.). Thecalculated IC₅₀ value is the concentration of the test compound thatcaused a 50% decrease in the maximal TNFα production.

Preferred compounds have an IC₅₀<1 uM in this assay.

Inhibition of Other Cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELISA kits (or other method ofdetection such as radioimmunoassay), for a particular cytokine,inhibition of IL-1beta, GM-CSF, IL-6 and IL-8 can be demonstrated forpreferred compounds (for example, see J. C. Lee et al., 1988, Int. J.Immunopharmacol., 10, 835).

All references cited in this application are incorporated herein byreference in their entirety.

1. A compound of the formula (I)

wherein: Ar¹ is chosen from rings (i), (ii) and (iii) below:

wherein one of A or B is nitrogen and the other is carbon, R¹ iscovalently attached to either A or B, and when nitrogen is N—R¹ thedouble bond between A and B is not present; is R¹ is chosen fromhydrogen, NO₂, —N(R^(c))₂, J-C(O)—N(R^(c))—, J-S(O)_(m)—N(R^(c))—, or R¹is chosen from C₁— alkyl, C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl or C₃₋₇cycloalkoxyl, C₁₋₅ alkylthiol or C₃₋₇ cycloalkylthiol, C₁₋₅ acyl, C₁₋₅alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₂₋₅ alkenyl, C₂₋₅alkynyl, heterocycle, heteroaryl and nitrile, each of the aforementionedwhere possible are optionally partially or fully halogenated or areoptionally further substituted with alkylsulfonylamino, alkoxyl, amino,alkylamino, dialkylamino, hydroxyl, oxo, nitro or nitrile; or R¹ is,where P can be 0, >CR⁹ or >NR⁹

wherein z is 1 to 4; R⁹ is chosen from C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅alkoxyl or C₃₋₇ cycloalkoxyl, C₁₋₅ alkylthiol or C₃₋₇ cycloalkylthiol,C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₂₋₅alkenyl, C₂₋₅ alkynyl, heterocycle, heteroaryl and nitrile, each of theaforementioned where possible are optionally partially or fullyhalogenated or are optionally further substituted withalkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino, hydroxyl,oxo, nitro or nitrile; R is chosen from hydrogen, halogen, C₁₋₅ alkyl,C₁₋₅ alkoxy, C₁₋₅ alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyl, oxo,C₁₋₅ alkylS(O)_(m)— and amino optionally mono- or di-substituted by C₁₋₅alkyl, aryl or aryl C₁₋₅ alkyl;

wherein R^(1′) is chosen from hydrogen, C₁₋₅ alkylS(O)_(m)—, C₁₋₆ alkyl,C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl or C₃₋₇ cycloalkoxyl, C₁₋₅ alkylthiol C₃₋₇cycloalkylthiol, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₂₋₅alkenyl, C₂₋₅ alkynyl, heterocycle, heterocycleC₁₋₆ alkyl, heteroaryl,heteroarylC₁₋₆ alkyl and nitrile, each of the aforementioned wherepossible are optionally partially or fully halogenated or are optionallyfurther substituted with alkylsulfonylamino, alkoxyl, amino, alkylamino,dialkylamino, hydroxyl, oxo, nitro or nitrile; R^(2′) is chosen fromnitrile, C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, NH₂—C(O)—(CH₂)_(n)—, H,halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₁₋₅ alkylC₁₋₅ alkoxy, hydroxy,hydroxy C₁₋₅ alkyl and amino optionally mono- or di-substituted by C₁₋₅alkyl, aryl or aryl C₁₋₅ alkyl;

wherein c is a benzo ring fused to ring d which is a 5-7 memberedheterocyclic ring; each R^(x) is chosen from C₁₋₆ alkyl or C₃₋₇cycloalkyl each being optionally substituted by C₁₋₃ alkyl andoptionally partially or fully halogenated, C₁₋₄ acyl, aroyl, C₁₋₄alkoxy, which may optionally be partially or fully halogenated, halogen,C₁₋₆ alkoxycarbonyl, carbocyclesulfonyl and —SO₂—CF₃; each J isindependently chosen from C₁₋₁₀ alkyl and carbocycle each optionallysubstituted by R^(b); R^(b) is chosen from hydrogen, C₁₋₅ alkyl,hydroxyC₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, carbocycle, heterocycle,heteroaryl, C₁₋₅ alkoxy, C₁₋₅ alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅dialkylamino, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅acylamino, each of the aforementioned are optionally partially or fullyhalogenated, or R^(b) is chosen from C₁₋₅ alkylsulphonylamino, hydroxy,oxo, halogen, nitro and nitrile; Q is a N or CR^(p); Y is >CR^(p)R^(v),—CR^(p)═C(R^(v))—, —O—, —N(R^(c))- or >S(O)_(m); each R^(c), R^(p),R^(v) and R^(y) are each independently hydrogen or C₁₋₅ alkyl; X is—CH₂—, —N(R^(c))—, —O— or —S—; W is N or CH; each m independently 0, 1or 2; n is 1-4; each R³, R⁴ and R⁵ are independently chosen fromhydrogen, C₁₋₆ alkyl and halogen; R⁶ is optionally attached at aposition ortho or meta to the N atom of the indicated ring, and ischosen from a bond, —O—, —O—(CH₂)₁₋₅—, >C(O), —NH—, —C(O)—NH—, —S—, C₁₋₅alkyl branched or unbranched, C₂₋₅ alkenyl, C₁₋₃ acyl, C₁₋₃ alkyl(OH),heterocycle selected from morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl and tetrahydrofuranyl, heteroaryl selected from pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, isoxazolyl, thiazolyl, oxazolyl and isothiazolyl or aryleach alkyl, alkenyl, acyl, heterocycle, heteroaryl and aryl areoptionally substituted by one to three hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₅ alkoxycarbonyl, —NR⁷R⁸ or NR⁷R⁸—C(O)—; wherein each R⁶ isfurther optionally covalently attached to groups chosen from: hydrogen,NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy, C₁₋₃ alkoxy,phenoxy, benzyloxy, arylC₀₋₄ alkyl, heteroaryl C₀₋₄ alkyl andheterocycle C₀₋₄alkyl, each above-listed heterocycle, heteroaryl andaryl group is optionally substituted by one to three hydroxy, oxo, C₁₋₄alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, NR⁷R⁸—C(O)— or C₁₋₄ acyl; eachR⁷ and R⁸ are independently hydrogen, phenylC₀₋₃alkyl optionallysubtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, or R⁷ and R⁸are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched alkyl optionallysubstituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino; orthe pharmaceutically acceptable salts and/or isomers thereof.
 2. Thecompound according to claim 1 and wherein: if Ar¹ is (i) then: R¹ ischosen from hydrogen, C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl andnitrile, each of the aforementioned where possible are optionallypartially or fully halogenated or are optionally further substitutedwith alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,hydroxyl, oxo, nitro or nitrile; R² is chosen from hydrogen, halogen,C₁₋₅ alkyl, C₁₋₅ alkoxy, C₁₋₅ alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅alkyl, oxo, C₁₋₅ alkylS(O)_(m)— and amino optionally mono- ordi-substituted by C₁₋₅ alkyl, phenyl or phenyl C₁₋₅ alkyl; if Ar¹ is(ii) then: R^(1′) is chosen from H, C₁₋₆ alkyl, C₁₋₅ alkylS(O)_(m)—,C₁₋₅ alkoxyl C₁₋₅ alkylthiol, NH₂—C(O)—(CH₂)—, heterocycle,heterocycleC₁₋₆alkyl, heteroaryl and nitrile, each of the aforementionedwhere possible are optionally partially or fully halogenated or areoptionally further substituted with alkylsulfonylamino, alkoxyl, amino,alkylamino, dialkylamino, hydroxyl, oxo, nitro and nitrile; R^(2′) ischosen from C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl and C₁₋₅alkoxy; or if Ar¹ is (iii) then: ring d is a 5-6 membered heterocyclicring; and z is 1 to
 2. 3. The compound according to claim 2 and wherein:if Ar¹ is (i) then: R¹ is chosen from hydrogen, C₁₋₆ alkyl or nitrile;R² is chosen from hydrogen, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, oxo orC₁₋₅ alkylS(O)_(m)—; if Ar¹ is (ii) then: R^(1′) is chosen fromhydrogen, C₁₋₆ alkyl, C₁₋₅ alkylS(O)_(m)—, C₁₋₅ alkoxyl C₁₋₅ alkylthiol,NH₂—C(O)—(CH₂)_(n)—, morpholino C₁₋₆ alkyl, heteroaryl chosen frompyrazole, triazole, imidazole and tetrazole, and nitrile; R^(2′) ischosen from C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl and C₁₋₅alkoxy; or if Ar¹ is (iii) then: ring d is a 5-6 membered heterocyclicring such that rings c and d fuse to form the following:

where each R is independently H or C₁₋₃ alkyl.
 4. The compound accordingto claim 3 and wherein: J is chosen from C₁₋₁₀ alkyl, aryl and C₃₋₇cycloalkyl each optionally substituted by R^(b); R^(x) is independentlychosen from C₁₋₆ alkyl which may optionally be partially or fullyhalogenated, C₃₋₆ cycloalkyl optionally substituted by C₁₋₃ alkyl andoptionally partially or fully halogenated, acetyl, aroyl, C₁₋₄ alkoxy,which may optionally be partially or fully halogenated, halogen,methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃; R^(b) is chosen fromhydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, C₃₋₈ cycloalkylC₀₋₂alkyl, aryl, C₁₋₅ alkoxy, C₁₋₅ alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅dialkylamino, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅acylamino, C₁₋₅ sulphonylamino, hydroxy, halogen, trifluoromethyl,nitro, nitrile, or R^(b) is chosen from heterocycle chosen frompyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinyl sulfone, dioxalanyl, piperidinyl,piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide,pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxideand tetramethylene sulfone and heteroaryl chosen from aziridinyl,thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl,naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl,purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl,tubercidinyl, oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl; and R⁷is hydrogen.
 5. The compound according to claim 4 and wherein: Y is —O—,—S—, —NH—, —N(CH₂CH₃)— or —N(CH₃)—; X is —N(R^(a))- or —O—; Q is CH;each R³, R⁴ and R⁵ are hydrogen; R^(b) is chosen from hydrogen, C₁₋₅alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, C₃₋₈ cycloalkylC₀₋₂ alkyl, aryl, C₁₋₅alkoxy, C₁₋₅ alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅ dialkylamino, C₁₋₅acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₁₋₅sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile orR^(b) is chosen from; heterocycle chosen from pyrrolidinyl, pyrrolinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone,1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylenesulfide, pentamethylene sulfoxide, pentamethylene sulfone,tetramethylene sulfide, tetramethylene sulfoxide and tetramethylenesulfone and heteroaryl chosen from aziridinyl, thienyl, furanyl,isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl,pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl,indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl.
 6. The compoundaccording to claim 5 and wherein: Y is —O—, —S— or —N(CH₃)—; R⁶ ispresent, and is chosen from a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—,C₁₋₅ alkyl branched or unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH),heterocycle selected from morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl and tetrahydrofuranyl, or aryl chosen from phenyl andnaphthyl, each alkyl, alkenyl, heterocycle and aryl are optionallysubstituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono ordiC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl; wherein each R⁶ isfurther optionally covalently attached to groups chosen from: hydrogen,NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy, C₁₋₃ alkoxy,phenoxy, benzyloxy, phenylC₀₋₄ alkyl, piperazinylC₀₋₄ alkyl, piperidinylC₀₋₄alkyl, pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄ alkyl,tetrahydrofuranylC₀₋₄ alkyl, triazolyl C₀₋₄alkyl, imidazolyl C₀₋₄alkyland pyridinyl C₀₋₄alkyl, each abovelisted heterocycle, heteroaryl andphenyl group is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, —NR⁷R⁸, NR⁷R⁸—C(O)— orC₁₋₄ acyl; each R⁷ and R⁸ are independently hydrogen, phenylC₀₋₃alkyloptionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, orR⁷ and R⁸ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched alkyloptionally substituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkylamino.
 7. The compound according to claim 6 and wherein: X is —O—; Y is—N(CH₃)—; R⁶ is chosen from a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—,C₁₋₅ alkyl branched or unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH),heterocycle selected from morpholinyl, piperazinyl, piperidinyl andpyrrolidinyl or phenyl, each alkyl, alkenyl, heterocycle and phenyl areoptionally substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy,mono or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl; wherein eachR⁶ is further optionally covalently attached to groups chosen from:hydrogen, —NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, benzyloxy,phenylC₀₋₄ alkyl, piperazinylC₀₋₄ alkyl, piperidinyl C₀₋₄alkyl,pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄ alkyl, triazolyl C₀₋₄alkyl,imidazolyl C₀₋₄alkyl and pyridinyl C₀₋₄alkyl, each above-listedheterocycle, heteroaryl and phenyl group is optionally substituted byone to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl,amino, NR⁷R⁸—C(O)— or C₁₋₄ acyl; each R⁷ and R⁸ are independentlyhydrogen, phenylC₀₋₂alkyl optionally subtituted by halogen, C₁₋₃ alkylor diC₁₋₅ alkyl amino, or R⁷ and R⁸ are C₁₋₅ branched or unbranchedalkyl optionally substituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃alkyl amino; R^(b) is chosen from hydrogen, C₁₋₅ alkyl, C₃₋₇cycloalkylC₀₋₂ alkyl, aryl, C₁₋₅ alkoxy, amino, C₁₋₅ alkylamino, C₁₋₃dialkylamino, C₁₋₃ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ acyloxy, C₁₋₃acylamino, C₁₋₃ sulphonylamino, hydroxy, halogen, trifluoromethyl,nitro, nitrile; or R^(b) is chosen from pyrrolidinyl, pyrrolinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone, piperidinyl, piperazinyl, piperidinonyl, tetrahydropyrimidonyl,aziridinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl,pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl.
 8. The compound according to claim 7 and wherein: R⁶ ischosen from a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkylbranched or unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycleselected from morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl orphenyl, each alkyl, alkenyl, heterocycle and phenyl are optionallysubstituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono ordiC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl; wherein each R⁶ isfurther optionally covalently attached to groups chosen from: hydrogen,—NR⁷R⁸, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, benzyloxy, phenylC₀₋₄alkyl, piperazinyl, piperazinylC₁₋₂ alkyl, piperidinyl, piperidinylC₁₋₂alkyl, pyrrolidinyl, pyrrolidinyl C₁₋₂ alkyl, morpholinyl,morpholinylC₁₋₂ alkyl, triazolyl, triazolyl C₁₋₂alkyl, imidazolyl,imidazolyl C₁₋₂alkyl, pyridinyl and pyridinyl C₁₋₂alkyl, eachabove-listed heterocycle, heteroaryl and phenyl group is optionallysubstituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅alkoxycarbonyl, amino, NR⁷R⁸—C(O)— or C₁₋₄ acyl.
 9. The compoundaccording to claim 8 and wherein: R^(h) is chosen from hydrogen, C₁₋₅alkyl, C³⁻⁶ cycloalkylC₀₋₂ alkyl, phenyl, C₁₋₅ alkoxy, amino, C₁₋₅alkylamino, C₁₋₃ dialkylamino, C₁₋₃ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₃acyloxy, C₁₋₃ acylamino, hydroxy, halogen; or R^(b) is chosen frommorpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone, piperidinyl, piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyland pyridazinyl.
 10. The compound according to claim 9 and wherein:R^(h) is chosen from amino, C₁₋₅ alkylamino, C₁₋₃ dialkylamino; or R^(b)is chosen morpholinyl, piperidinyl and pyridinyl.
 11. The compoundaccording to claim 10 and wherein: R¹ is chosen from:


12. The compound according to any one of claims 1-11 and wherein: if Ar¹is (i), then Ar¹ is:

if Ar¹ is (ii), then Ar¹ is:

where R in these structures is C₁₋₅alkyl.
 13. A compound chosen from:1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (2-tert-butyl-5-methoxy-pyridin-4-yl)-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfinyl-phenyl)-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methanesulfonyl-phenyl)-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-oxo-1,2-dihydro-pyridin-3-yl)-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methyl-pyridin-3-yl)-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-cyano-2-methoxy-phenyl)-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methyl-pyridin-3-yl)-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-cyano-2-methoxy-phenyl)-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methanesulfinyl-phenyl)-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methyl-pyridin-3-yl)-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methanesulfinyl-phenyl)-amide1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-cyano-2-methoxy-phenyl)-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (2-tert-butyl-5-methanesulfinyl-pyridin-4-yl)-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide;1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(2-oxo-azetidin-1-yl)-phenyl]-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (2-amino-6-tert-butyl-3-methoxy-pyridin-4-yl)-amide;1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amideand1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide;or the pharmaceutically acceptable salts thereof.
 14. A pharmaceuticalcomposition containing a pharmaceutically effective amount of a compoundaccording to claim 1 and one or more pharmaceutically acceptablecarriers and/or adjuvants.
 15. A method of treating an oncologicaldisease comprising administering to a patient a pharmaceuticallyeffective amount of a compound according to claim
 1. 16. A method oftreating a disease or condition chosen from osteoarthritis,atherosclerosis, contact dermatitis, bone resorption diseases,reperfusion injury, asthma, multiple sclerosis, Guillain-Barre syndrome,Crohn's disease, ulcerative colitis, psoriasis, graft versus hostdisease, systemic lupus erythematosus, insulin-dependent diabetesmellitus, rheumatoid arthritis, toxic shock syndrome, Alzheimer'sdisease, diabetes, inflammatory bowel diseases, acute and chronic pain,stroke, myocardial infarction alone or following thrombolytic therapy,thermal injury, adult respiratory distress syndrome (ARDS), multipleorgan injury secondary to trauma, acute glomerulonephritis, dermatoseswith acute inflammatory components, acute purulent meningitis, syndromesassociated with hemodialysis, leukopherisis, granulocyte transfusionassociated syndromes, necrotizing entrerocolitis, restenosis followingpercutaneous transluminal coronary angioplasty, traumatic arthritis,sepsis, chronic obstructive pulmonary disease and congestive heartfailure, said method comprising administering to a patient apharmaceutically effective amount of a compound according to claim 1.